Tricyclic prodrugs

ABSTRACT

Prodrugs of galiellactone, and derivatives thereof, are provided by reacting the parent compound, e.g. galiellactone, with a thiol. Such drugs may be administered orally to treat cancer and other proliferative diseases.

CROSS-REFERENCE TO RELATED APPLICATION

This application is a divisional of U.S. patent application Ser. No.15/124,096 filed on Sep. 7, 2016, which is a U.S. National StageApplication of International Application No. PCT/EP2015/054754 filed onMar. 6, 2015, which claims priority to Swedish Patent Application No.SE1450263-7 filed on Mar. 7, 2014, the disclosures of all of which areincorporated herein by reference in their entireties.

TECHNICAL FIELD

The present invention relates to novel tricyclic compounds comprising aresidue of a thiol, pharmaceutical compositions comprising suchcompounds, and a method of treating or alleviating conditions, inparticular cancer, by use of such compounds.

BACKGROUND

Cancer is a heterogeneous disease. Accordingly any treatment should beadopted for given type of cancer as determined by the location andgenetic makeup of the tumor. However, although cancer is a heterogeneousdisease, all forms of cancer show some fundamental similaritiesincluding uncontrolled growth and self-renewal. So despite differentgenetic backgrounds different cancers have common traits and this is insome ways driven by the pattern of gene expression. Since many differentsignals, regardless of cause, converge on transcription factors, andsince the activation of transcription factors is a nodal point for genetranscription, transcription factors should be convergent targets fortreating cancer.

Transcription factors are essential cellular components mediatingdifferent extracellular signals, including developmental andenvironmental, by binding to transcription responsive elements in thegenome and thereby initiating the transcription of specific targetgenes. Aberrant transcription factor function is often associated withdifferent diseases and leads to either increased or excessive genetranscription. As many signals and activating mechanisms converge onsingle transcription factors they could make efficient drug targets,e.g. for treatment of cancer.

Latent cytoplasmic transcription factors (LCTFs) are transcriptionfactors that reside in the cytoplasm in an inactive form until they areactivated through an external signal often in the form of a cell surfacereceptor-ligand interaction. Among these transcription factors are thefamily of Signal Transducer and Activator of Transcription (STAT)proteins. The STAT proteins have dual roles as they can act as bothtransducers of signals through the cytoplasm and function astranscription factors in the nucleus.

STAT3 is one of 6 members of the STAT family of transcriptions factors.It is an approx. 770 amino acid long protein with 6 subunits or domains;N-terminal, coiled-coil, DNA-binding, linker, SH2 and transactivationdomains. STAT3 is activated by cytokine, growth factor and non-receptormediated signaling. The canonical mechanism of STAT3 activation iskinase mediated phosphorylation of tyrosine 705 (Y705) in the SH2domain. This triggers a reciprocal recognition of two SH2 domains ofSTAT3 monomers leading to the formation of a STAT3 dimer. This dimer istranslocated to the nucleus, aided by importins, and transcription oftarget genes, through binding to DNA, is activated. On its way to thenucleus STAT3 can be further modified through serine phosphorylation,lysine acetylation or Small Ubiquitin-like Modifier (SUMO) proteinattachment and these modifications serve to modulate the transcriptionalactivity of STAT3

STAT3 activation and dimerization through phosphorylation can beachieved through at least three responses. STAT3 can be phosphorylatedby JAK kinases that are constitutively bound to cytokine receptors. Uponligand binding, the receptors aggregate and the JAK2 proteins undergoreciprocal activation through phosphorylation and they can then recruitand activate STAT3 through binding to the SH2 domain. Alternativelygrowth factor receptors can directly recruit and associate with STAT3leading to STAT3 activation through their receptor tyrosine kinaseactivity. Finally, non-receptor kinases, e.g. Src family kinases andAbl, can also activate STAT3. In addition non-phosphorylated STAT3 canbe transported into the nucleus and participate in transcriptionprobably by binding to other proteins to form functional heteromerictranscription factors.

In the nucleus STAT3 can interact with several other proteins includingother transcription factors e.g. NF-κB.

STAT3 can also be activated by phosphorylation on serine 727 by variouskinases. This phosphorylation leads to enhanced transcriptionalactivity. Constitutively phosphorylated serine 727 is widespread incells from patients suffering from chronic lymphocytic leukemia (CLL).

Since STAT3 activation under normal conditions is transient, multiplenegative feedback systems exist. STAT3 signaling is tightly regulatedand it is not constitutively activated in normal tissue. Severalendogenous negative regulators for STAT3 signaling have been found andthese include Suppressor of cytokine signaling (SOCS, that bind to andinactivate JAKs) and protein inhibitor of activated STAT (PIAS). SOCS isalso a gene product of STAT3 transcription demonstrating this as anegative feedback loop. Loss of PIAS or SOCS function or reducedexpression will increase STAT3 activation and mutations of theseregulatory factors have been found in diseases related to increase STAT3signaling.

Finally STAT3 is dephosphorylated in the nucleus by differentphosphatases and the dephophorylated STAT3 monomers are transported outof the nucleus where they once again reside latent.

The target genes of STAT3 transcription are involved in cell growth andcell cycle regulation (e.g. Cyclin D1, c-Myc, p27), apoptosis (e.g.Mcl-1, survivin, Bcl-2, and Bcl-xL), angiogenesis (VEGF) and metastasis(e.g. MMP-2, MMP-3).

STAT3 can be activated by cytokines and growth factors including IL6,LIF, IL-10, IL-1, IL-12, EGF, TGFalpha, PDGF and G-CSF and varioustyrosine and serine kinases including JAK, JAK2, JAK3, TYK2, Src, Src,Lck, Hck, Lyn, Fyn, Fgr, EGFR, ErbB-2, Grb2, JNK, P38MAPK and ERK.

STAT3 is an experimentally validated target in several cancer forms,including leukemia, lymphomas, multiple myeloma, breast cancer, prostatecarcinoma, lung cancer (non-small-cell), renal cell carcinoma lungcancer, hepatocellular carcinoma, cholangiocarcinoma, ovarian carcinoma,pancreatic adenocarcinoma, melanoma, head and neck squamous cellcarcinoma (Johnston, P. A; Grandis, J. R. Mol Interv. 2011 11(1):18-26). STAT3 signaling is involved in proliferation, survival,metastasis, drug resistance and migration of cancer cells and it alsolinks inflammation and cancer. This has been demonstrated in numerousstudies in vitro, using primary cells or immortalized cell lines, or invivo using xenograft models (cf. e.g. Sansone, P; Bromberg, J. J ClinOncol. 2012; 30(9):1005-14, and Miklossy, G.; Hilliard, T. S.; Turkson,J. Nat Rev Drug Discov. 2013 12(8):611-29) and as such is believed to bean ideal target for cancer therapy (Yu, H.; Lee, H.; Herrmann, A.;Buettner, R.; Jove, R. Nat Rev Cancer. 2014 14(11):736-46.

The sensitivity of many cancer cell lines to STAT3 inhibition indicatesan oncogene signaling dependence.

Inflammation and immunity are also important parts of cancer etiology.Cancer cells can promote inflammation in the tumor microenvironment andavoid the innate immune system. STAT3 signaling plays an important dualrole in this process. STAT3 is activated by pro-inflammatory cytokinesignaling and STAT3 activation opposes T-helper cell anti-tumorresponses. Ablation of STAT3 signaling leads to a potent immunologicalantitumor response. STAT3 is more activated in tumor infiltrating immunecells than in normal tissue and targeting STAT3 causes therapeuticantitumor immunity.

In summary aberrant and deregulated STAT3 promotes cell proliferationand cell survival in both solid and hematological tumors, includingbreast, lung, brain, colon, prostate, lymphoma and leukemia. Directinhibitors of STAT3 or inhibitors of STAT3 signaling are thus deemed tobe able to mitigate or cure those pathological states.

The treatments for prevention, revocation or reduction of diseases likee.g. cancer are in many ways insufficient. Hence, compounds effective inmodulating or inhibiting the above described STAT signaling would bedesired.

The direct inhibition of STAT3 can be achieved by inhibiting theprotein-protein interaction involved in STAT3 dimerization (STAT3 is adimer of two proteins) or by blocking the protein-DNA interactionrequired for STAT3 binding to DNA for the initiation of transcription.Alternatively the production (biosynthesis) of STAT3 can be blocked.

The alternative to direct STAT3 inhibition is to inhibit upstreammolecules in the signaling cascade responsible for STAT3 activation(e.g. the JAK kinases). The drawback with this approach is that thereare multiple ways to activate STAT3.

The STAT3 SH2 has been targeted with peptidomimetics and non-peptidesmall molecules (e.g. S3I-M2001) to block STAT3-STAT3 dimerization andDNA binding has been blocked with oligodeoxynucleotide decoys while theproduction of STAT3 has been inhibited by antisense.

(−)-Galiellalactone is a natural product isolated from wood-inhabitingfungi with submicromolar inhibition of IL-6/STAT3 signaling.

In U.S. Pat. No. 6,512,007 use of galiella lactone as a pharmaceuticalfor the treatment of e.g. inflammatory processes is disclosed.

The biological effect of (−)-galiellalactone seemingly is due to adirect inhibition of the binding of STAT3-dimers to their regulatoryelements (Weidler et al in FEBS Letters 2000, 484, 1-6). Based on thisproposed mechanism of action, galiellalactone has been evaluated as ananti-cancer agent. Hellsten et al reported in Prostate 68:269-280 (2008)that galiellalactone inhibits the proliferation of STAT3 expressingDU145 prostate cancer cells. Further, Hellsten et al (“Targeting STAT3in prostate cancer: Identification of STAT3 as a direct target of thefungal metabolite galiellalactone” Nicholas Don-Doncow, Zilma Escobar,Martin Johansson, Eduardo Muñoz, Olov Sterner, Anders Bjartell, RebeckaHellsten. AACR-NCI-EORTC International Conference on Molecular Targetsand Cancer Therapeutics, October 19-23, 2013, Boston, Mass. Abstract nrC229; Don-Doncow, N.; Escobar, Z.; Johansson, M.; Kjellström, S.;Garcia, V.; Munoz, E.; Sterner, O.; Bjartell, A.; Hellsten, R. J BiolChem. 2014 289(23):15969-78) have shown that galiellalactone bindsdirectly and covalently to STAT3, thus inhibiting the transcriptionalactivity. Galiellalactone is thus a candidate drug for treatment ofcancer.

However, galiellalactone has been found to display limited plasmaexposure upon oral administration and as such is deemed to not representa suitable drug for oral delivery. Hence, ways of improving the oralbioavailability and/or other druglike properties of galiellalactone arewarranted.

Attempts to modify the activity and properties of galiellalactone havebeen reported in the art. Nussbaum et al reported in Eur. J. Org. Chem.2004, 2783-2790 on the modification of individual functional groups of(−)-galiellalactone. Most of the resulting analogues, however, turnedout to be completely inactive or much less active than(−)-galiellalactone. Especially, modifications of the conjugated doublebond were reported to produce inactive compounds. In PCT/EP2011/062243preparation and use of novel tricylic compounds, based on agaliellalactone scaffold, that inhibit STAT3 and NF-kB signaling aredisclosed.

However none of these modified derivatives has been reported to overcomethe shortcoming of galiellalactone when administered orally. Thus, thereis a need in the art for inhibitors STAT3 having improved drug likeproperties to achieve sufficient exposure and dosing regimes.

SUMMARY

The present invention seeks to mitigate, alleviate, circumvent oreliminate at least one, such as one or more, of the above-identifieddeficiencies by providing a compound, according to an aspect, a compoundaccording to formula (I)

wherein

R₁ and R₁′ are independently selected from the group consisting of H,C1-5 alkyl, C1-5 fluoroalkyl, halo, C3-8 non-aromatic carbocycle, C0-5alkyleneOC0-5 alkyl, C0-3 alkyleneOC1-5 fluoroalkyl, C0-3alkyleneOC(O)C1-5 alkyl, OC2-3 alkyleneN(C0-5 alkyl)₂ in which the C0-5alkyl may be the same or different, C0-3 alkyleneNHC0-5 alkyl, C0-3alkyleneN(C1-5 alkyl)₂ in which the C1-5 alkyl may be the same ordifferent, C0-3 alkyleneN(C0-5 alkyl)C(O)C1-5 alkyl, C0-3alkyleneNHaryl, wherein the aryl is unsubstituted or substituted with aone or several substituents independently selected from the groupconsisting of C1-5 alkyl, C1-5 fluoroalkyl, halo, C0-5 alkyleneOC0-5alkyl, nitro, cyano and N(C0-5 alkyl)₂ in which the C0-5 alkyl may bethe same or different, C0-3 alkyleneNHheteroaryl, wherein saidheteroaryl is a 5- or 6-membered heteroaryl, said heteroaryl beingunsubstituted or substituted with a one or several independentlyselected C1-5 alkyl groups, C0-3 alkyleneC(O)NHC0-5 alkyl, C0-3alkyleneC(O)N(C1-5 alkyl)₂ in which the C1-5 alkyl may be the same ordifferent, C0-3 alkyleneC(O)N(C4-5 alkylene), C0-3 alkyleneC(O)OC0-5alkyl, a 3- to 8-membered non-aromatic heterocycle, C0-3 alkylene aryl,wherein the aryl is unsubstituted or substituted with a one or severalsubstituents independently selected from the group consisting of C1-5alkyl, C1-5 fluoroalkyl, halo, C0-5 alkyleneOC0-5 alkyl, nitro, cyanoand N(C0-5 alkyl)₂ in which the C0-5 alkyl may be the same or different,C0-3 alkylene heteroaryl, wherein said heteroaryl is a 5- or 6-memberedheteroaryl, said heteroaryl being unsubstituted or substituted with aone or several independently selected C1-5 alkyl groups, halo, C0-1alkylene cyano, SC0-5 alkyl, C0-3 alkyleneSO₂C0-5 alkyl, nitro,C(O)C0-C5 alkyl, C(O)C1-C5 fluoroalkyl, N(C0-C3 alkyl)SO₂C1-C5 alkyl,and N(C0-C5 alkyl)SO₂C1-5 fluoroalkyl;

R₂ and R₂′ are independently selected from the group consisting of H,C1-5 alkyl, C1-5 fluoroalkyl, halo, C3-8 non-aromatic carbocycle, C0-5alkyleneOC0-5 alkyl, C0-3 alkyleneOC1-5 fluoroalkyl, C0-3alkyleneOC(O)C1-5 alkyl, OC2-3 alkyleneN(C0-5 alkyl)₂ in which the C0-5alkyl may be the same or different, C0-3 alkyleneNHC0-5 alkyl, C0-3alkyleneN(C1-5 alkyl)₂ in which the C1-5 alkyl may be the same ordifferent, C0-3 alkyleneN(C0-5 alkyl)C(O)C1-5 alkyl, C0-3alkyleneNHaryl, wherein the aryl is unsubstituted or substituted with aone or several substituents independently selected from the groupconsisting of C1-5 alkyl, C1-5 fluoroalkyl, halo, C0-5 alkyleneOC0-5alkyl, nitro, cyano and N(C0-5 alkyl)₂ in which the C0-5 alkyl may bethe same or different, C0-3 alkyleneNHheteroaryl, wherein saidheteroaryl is a 5- or 6-membered heteroaryl, said heteroaryl beingunsubstituted or substituted with a one or several independentlyselected C1-5 alkyl groups, C0-3 alkyleneC(O)NHC0-5 alkyl, C0-3alkyleneC(O)N(C1-5 alkyl)₂ in which the C1-5 alkyl may be the same ordifferent, C0-3 alkyleneC(O)N(C4-5 alkylene), C0-3 alkyleneC(O)OC0-5alkyl, a 3- to 8-membered non-aromatic heterocycle, C0-3 alkylene aryl,wherein the aryl is unsubstituted or substituted with a one or severalsubstituents independently selected from the group consisting of C1-5alkyl, C1-5 fluoroalkyl, halo, C0-5 alkyleneOC0-5 alkyl, nitro, cyanoand N(C0-5 alkyl)₂ in which the C0-5 alkyl may be the same or different,C0-3 alkylene heteroaryl, wherein said heteroaryl is a 5- or 6-memberedheteroaryl, said heteroaryl being unsubstituted or substituted with aone or several independently selected C1-5 alkyl groups, halo, C0-1alkylene cyano, SC0-5 alkyl, C0-3 alkyleneSO₂C0-5 alkyl, nitro,C(O)C0-C5 alkyl, C(O)C1-C5 fluoroalkyl, N(C0-C3 alkyl)SO₂C1-C5 alkyl,and N(C0-C5 alkyl)SO₂C1-5 fluoroalkyl;

R₃ and R₃′ are independently selected from the group consisting of H,C1-5 alkyl, C1-5 fluoroalkyl, halo, C3-8 non-aromatic carbocycle, C0-5alkyleneOC0-5 alkyl, C0-3 alkyleneOC1-5 fluoroalkyl, C0-3alkyleneOC(O)C1-5 alkyl, OC2-3 alkyleneN(C0-5 alkyl)₂ in which the C0-5alkyl may be the same or different, C0-3 alkyleneNHC0-5 alkyl, C0-3alkyleneN(C1-5 alkyl)₂ in which the C1-5 alkyl may be the same ordifferent, C0-3 alkyleneN(C0-5 alkyl)C(O)C1-5 alkyl, C0-3alkyleneNHaryl, wherein the aryl is unsubstituted or substituted with aone or several substituents independently selected from the groupconsisting of C1-5 alkyl, C1-5 fluoroalkyl, halo, C0-5 alkyleneOC0-5alkyl, nitro, cyano and N(C0-5 alkyl)₂ in which the C0-5 alkyl may bethe same or different, C0-3 alkyleneNHheteroaryl, wherein saidheteroaryl is a 5- or 6-membered heteroaryl, said heteroaryl beingunsubstituted or substituted with a one or several independentlyselected C1-5 alkyl groups, C0-3 alkyleneC(O)NHC0-5 alkyl, C0-3alkyleneC(O)N(C1-5 alkyl)₂ in which the C1-5 alkyl may be the same ordifferent, C0-3 alkyleneC(O)N(C4-5 alkylene), C0-3 alkyleneC(O)OC0-5alkyl, a 3- to 8-membered non-aromatic heterocycle, C0-3 alkylene aryl,wherein the aryl is unsubstituted or substituted with a one or severalsubstituents independently selected from the group consisting of C1-5alkyl, C1-5 fluoroalkyl, halo, C0-5 alkyleneOC0-5 alkyl, nitro, cyanoand N(C0-5 alkyl)₂ in which the C0-5 alkyl may be the same or different,C0-3 alkylene heteroaryl, wherein said heteroaryl is a 5- or 6-memberedheteroaryl, said heteroaryl being unsubstituted or substituted with aone or several independently selected C1-5 alkyl groups, halo, C0-1alkylene cyano, SC0-5 alkyl, C0-3 alkyleneSO₂C0-5 alkyl, nitro,C(O)C0-C5 alkyl, C(O)C1-C5 fluoroalkyl, N(C0-C3 alkyl)SO₂C1-C5 alkyl,and N(C0-C5 alkyl)SO₂C1-5 fluoroalkyl;

R₄ and R₄′ are independently selected from the group consisting of H,C1-5 alkyl, C1-5 fluoroalkyl, halo, C3-8 non-aromatic carbocycle, C0-5alkyleneOC0-5 alkyl, C0-3 alkyleneOC1-5 fluoroalkyl, C0-3alkyleneOC(O)C1-5 alkyl, OC2-3 alkyleneN(C0-5 alkyl)₂ in which the C0-5alkyl may be the same or different, C0-3 alkyleneNHC0-5 alkyl, C0-3alkyleneN(C1-5 alkyl)₂ in which the C1-5 alkyl may be the same ordifferent, C0-3 alkyleneN(C0-5 alkyl)C(O)C1-5 alkyl, C0-3alkyleneNHaryl, wherein the aryl is unsubstituted or substituted with aone or several substituents independently selected from the groupconsisting of C1-5 alkyl, C1-5 fluoroalkyl, halo, C0-5 alkyleneOC0-5alkyl, nitro, cyano and N(C0-5 alkyl)₂ in which the C0-5 alkyl may bethe same or different, C0-3 alkyleneNHheteroaryl, wherein saidheteroaryl is a 5- or 6-membered heteroaryl, said heteroaryl beingunsubstituted or substituted with a one or several independentlyselected C1-5 alkyl groups, C0-3 alkyleneC(O)NHC0-5 alkyl, C0-3alkyleneC(O)N(C1-5 alkyl)₂ in which the C1-5 alkyl may be the same ordifferent, C0-3 alkyleneC(O)N(C4-5 alkylene), C0-3 alkyleneC(O)OC0-5alkyl, a 3- to 8-membered non-aromatic heterocycle, C0-3 alkylene aryl,wherein the aryl is unsubstituted or substituted with a one or severalsubstituents independently selected from the group consisting of C1-5alkyl, C1-5 fluoroalkyl, halo, C0-5 alkyleneOC0-5 alkyl, nitro, cyanoand N(C0-5 alkyl)₂ in which the C0-5 alkyl may be the same or different,C0-3 alkylene heteroaryl, wherein said heteroaryl is a 5- or 6-memberedheteroaryl, said heteroaryl being unsubstituted or substituted with aone or several independently selected C1-5 alkyl groups, halo, C0-1alkylene cyano, SC0-5 alkyl, C0-3 alkyleneSO₂C0-5 alkyl, nitro,C(O)C0-C5 alkyl, C(O)C1-C5 fluoroalkyl, N(C0-C3 alkyl)SO₂C1-C5 alkyl,and N(C0-C5 alkyl)SO₂C1-5 fluoroalkyl;

R₅ is selected from the group consisting of H, C1-5 alkyl, C1-5fluoroalkyl, C(O)C1-5 alkyl, C2-3 alkyleneN(C0-5 alkyl)₂ in which theC0-5 alkyl may be the same or different, C(O)N(0-5 alkyl)₂ in which theC0-5 alkyl may be the same or different, C(O)aryl, wherein the aryl isunsubstituted or substituted with a one or several substituentsindependently selected from the group consisting of C1-5 alkyl, C1-5fluoroalkyl, halo, C0-5 alkyleneOC0-5 alkyl, nitro, cyano and N(C0-5alkyl)₂ in which the C0-5 alkyl may be the same or different,C(O)heteroaryl, wherein said heteroaryl is a 5- or 6-memberedheteroaryl, said heteroaryl being unsubstituted or substituted with aone or several independently selected C1-5 alkyl groups,C(O)C1-C3alkylenearyl, wherein the aryl is unsubstituted or substitutedwith a one or several substituents independently selected from the groupconsisting of C1-5 alkyl, C1-5 fluoroalkyl, halo, C0-5 alkyleneOC0-5alkyl, nitro, cyano and N(C0-5 alkyl)₂ in which the C0-5 alkyl may bethe same or different, and C(O)C1-C3alkyleneheteroaryl, wherein saidheteroaryl is a 5- or 6-membered heteroaryl, said heteroaryl beingunsubstituted or substituted with a one or several independentlyselected C1-5 alkyl groups; and

R₆ is selected from the group consisting of H, C1-8 alkyl, C1-8fluoroalkyl, C3-C8 alkyleneN(C1-5 alkyl)₂ in which the C1-5 alkyl may bethe same or different, C2-5 alkyleneOC0-5 alkyl, C2-3 alkyleneOC1-5fluoroalkyl, C2-3 alkyleneOC(O)C1-5 alkyl, C3-5 alkyleneNHC0-5 alkyl,C2-3 alkyleneN(C0-5 alkyl)C(O)C1-5 alkyl, C2-5 alkyleneNHaryl, whereinthe aryl is unsubstituted or substituted with a one or severalsubstituents independently selected from the group consisting of C1-5alkyl, C1-5 fluoroalkyl, halo, C0-5 alkyleneOC0-5 alkyl, nitro, cyano,and N(C0-5 alkyl)₂ in which the C0-5 alkyl may be the same or different,C2-5 alkyleneNHheteroaryl, wherein said heteroaryl is a 5- or 6-memberedheteroaryl, said heteroaryl being unsubstituted or substituted with aone or several independently selected C1-5 alkyl groups, C1-3alkyleneC(O)NHC0-5 alkyl, C1-3 alkyleneC(O)N(C1-5 alkyl)₂ in which theC1-5 alkyl may be the same or different, C1-3 alkyleneC(O)N(C4-5alkylene), C1-3 alkyleneC(O)OC0-5 alkyl, a 3- to 8-membered non-aromaticheterocycle, C2-3 alkylene aryl, wherein the aryl is unsubstituted orsubstituted with a one or several substituents independently selectedfrom the group consisting of C1-5 alkyl, C1-5 fluoroalkyl, halo, C0-5alkyleneOC0-5 alkyl, nitro, cyano and N(C0-5 alkyl)₂ in which the C0-5alkyl may be the same or different, C1-3 alkylene heteroaryl, whereinsaid heteroaryl is a 5- or 6-membered heteroaryl, said heteroaryl beingunsubstituted or substituted with a one or several independentlyselected C1-5 alkyl groups, C1-3 alkyleneSO₂C0-5 alkyl, C1-5alkyleneSO₃H, aryl, wherein the aryl is unsubstituted or substitutedwith a one or several substituents independently selected from the groupconsisting of C1-5 alkyl, C1-5 fluoroalkyl, halo, C0-5 alkyleneOC0-5alkyl, nitro, cyano and N(C0-5 alkyl)₂ in which the C0-5 alkyl may bethe same or different, heteroaryl, wherein said heteroaryl is a 5- or6-membered heteroaryl, said heteroaryl being unsubstituted orsubstituted with a one or several independently selected C1-5 alkylgroups, and moieties according to formula (II),

wherein the waved line indicates the point of attachment to the sulfuratom in formula (I);

A is a C1-5 alkylene;

D is a bond a phenylene, or a heteroarylene, wherein said heteroaryleneis a 5- or 6-membered heteroarylene;

E is a bond or a C1-5 alkylene;

X is NC0-C5 alkyl or “O” (oxygen);

R7 is selected from the group consisting of H, provided that X is NC0-C5alkyl, R7 is not to be H if X is “O” (oxygen), C1-C10 alkyl, C1-5alkyleneN(C1-5 alkyl)₂ in which the C1-5 alkyl may be the same ordifferent, C0-3 alkylene aryl, wherein the aryl is unsubstituted orsubstituted with a one or several substituents independently selectedfrom the group consisting of C1-5 alkyl, C1-5 fluoroalkyl, halo, C0-5alkyleneOC0-5 alkyl, nitro, cyano and N(C0-5 alkyl)₂ in which the C0-5alkyl may be the same or different, C1-3 alkylene heteroaryl, whereinsaid heteroaryl is a 5- or 6-membered heteroaryl, said heteroaryl beingunsubstituted or substituted with a one or several independentlyselected C1-5 alkyl groups, an amino acid residue selected from thegroup consisting alanine, arginine, asparagine, aspartic acid, cysteine,glutamine, glutamic acid, glycine, histidine, isoleucine, leucine,lysine; methionine, phenylalanine, proline, threonine, tryptophan,tyrosine and valine, which amino acid residue is connected to the moietyaccording to formula (II) at the N-terminal of the amino acid residueand optionally esterfied at the C-terminal with a C1-5 monohydricalkanol, and a di-, a tri-, or a tetrapeptide residue, wherein the aminoacid residues in said peptide residue are independently selected fromthe group consisting alanine, arginine, asparagine, aspartic acid,cysteine, glutamine, glutamic acid, glycine, histidine, isoleucine,leucine, lysine; methionine, phenylalanine, proline, threonine,tryptophan, tyrosine and valine, the peptide residue being connected tothe moiety according to formula (II) at the N-terminal of the peptideand optionally esterfied at the C-terminal with a C1-5 monohydricalkanol; and

R₈ is selected from the group consisting of C(O)C1-C6 alkyl, C(O)OC1-C6alkyl, C(O)C0-3 alkylene aryl, wherein the aryl is unsubstituted orsubstituted with a one or several substituents independently selectedfrom the group consisting of C1-5 alkyl, C1-5 fluoroalkyl, halo, C0-5alkyleneOC0-5 alkyl, nitro, cyano and N(C0-5 alkyl)₂ in which the C0-5alkyl may be the same or different, C(O)C0-3 alkylene heteroaryl,wherein said heteroaryl is a 5- or 6-membered heteroaryl, saidheteroaryl being unsubstituted or substituted with a one or severalindependently selected C1-5 alkyl groups, an amino acid residue selectedfrom the group consisting alanine, arginine, asparagine, aspartic acid,cysteine, glutamine, glutamic acid, glycine, histidine, isoleucine,leucine, lysine; methionine, phenylalanine, proline, threonine,tryptophan, tyrosine and valine, which amino acid residue is connectedto the moiety according to formula (II) at the C-terminal of the aminoacid residue, and which amino acid residue optionally is N-acylated,wherein said acyl group is selected from the group consisting C(O)C1-C6alkyl, and C(O)C0-3 alkylene aryl, wherein the aryl is unsubstituted orsubstituted with a one or several substituents independently selectedfrom the group consisting of C1-5 alkyl, C1-5 fluoroalkyl, halo, C0-5alkyleneOC0-5 alkyl, nitro, cyano and N(C0-5 alkyl)₂ in which the C0-5alkyl may be the same or different, and a di-, a tri-, or a tetrapeptideresidue, wherein the amino acid residues in said peptide residue areindependently selected from the group consisting alanine, arginine,asparagine, aspartic acid, cysteine, glutamine, glutamic acid, glycine,histidine, isoleucine, leucine, lysine; methionine, phenylalanine,proline, threonine, tryptophan, tyrosine and valine, the peptide residuebeing connected to the moiety according to formula (II) at theC-terminal of the peptide, and the N-terminal of the peptide optionallybeing N-acelyated, wherein said acyl group is selected from the groupconsisting C(O)C1-C6 alkyl and C(O)C0-3 alkylene aryl, wherein the arylis unsubstituted or substituted with a one or several substituentsindependently selected from the group consisting of C1-5 alkyl, C1-5fluoroalkyl, halo, C0-5 alkyleneOC0-5 alkyl, nitro, cyano and N(C0-5alkyl)₂ in which the C0-5 alkyl may be the same or different;

as a free base, an acid in its non-charged protonated form, apharmaceutically acceptable addition salt, solvate, solvate of a saltthereof, a pure diastereomer, a pure enantiomer, a diastereomericmixture, a racemic mixture, a scalemic mixture, a correspondingtautomeric form resulting from a hydrogen shift between two hetero-atomsand/or the corresponding tautomeric form resulting from a keto-enoltautomerization.

According to another aspect, there is provided a pharmaceuticalcomposition comprising a compound according to formula (I) and at leastone pharmaceutically acceptable carrier or excipient. Such compound andcomposition are useful in therapy.

According to another aspect, compounds according to formula (I) andcompositions comprising such compounds are useful in the treatment ofSTAT3 signaling related disorders as well as in treatment of diseasesand disorders selected from the group consisting of: solid cancers,hematological cancers, benign tumors, hyperproliferative diseases,inflammations, autoimmune diseases, graft or transplant rejections,delayed physiological function of grafts or transplants,neurodegenerative diseases and viral infections, such as from solidcancers and hematological cancers.

Further, advantageous features of various embodiments of the inventionare defined in the dependent claims and within the detailed descriptionbelow.

DETAILED DESCRIPTION Definitions

In the context of the present application and invention, the followingdefinitions apply:

The term “addition salt” is intended to mean salts formed by theaddition of a pharmaceutical acceptable acid, such as organic orinorganic acids, or a pharmaceutical acceptable base. The organic acidmay be, but is not limited to, acetic, propanoic, methanesulfonic,benzenesulfonic, lactic, malic, citric, tartaric, succinic or maleicacid. The inorganic acid may be, but is not limited to, hydrochloric,hydrobromic, sulfuric, nitric acid or phosphoric acid. The base may be,but is not limited to, ammonia and hydroxides of alkali or alkalineearth metals. The term “addition salt” also comprises the hydrates andsolvent addition forms, such as hydrates and alcoholates.

As used herein, “halo” or “halogen” refers to fluoro, chloro, bromo, andiodo.

As used herein, “alkyl” used alone or as a suffix or prefix, is intendedto include both branched and straight chain saturated aliphatichydrocarbon groups having from 1 to 12 carbon atoms or if a specifiednumber of carbon atoms is provided then that specific number isintended. For example “C1-6 alkyl” denotes alkyl having 1, 2, 3, 4, 5 or6 carbon atoms. When the specific number denoting the alkyl group is theinteger 0 (zero), no alkyl group having from 1 to 12 carbon atoms ispresent and a hydrogen atom is instead present as the substituent. Forexample, “N(CO alkyl)₂” is equivalent to “NH₂” (amino), CO alkyl isequivalent to H (hydrogen), and OC0 alkyl is equivalent to OH (hydroxy).Examples of alkyl include, but are not limited to, methyl, ethyl,n-propyl, propyl, n-butyl, i-butyl, sec-butyl, t-butyl, pentyl, andhexyl.

As used herein, “alkylenyl” or “alkylene” used alone or as a suffix orprefix, is intended to include straight chain saturated aliphatichydrocarbon groups having from 1 to 12 carbon atoms or if a specifiednumber of carbon atoms is provided then that specific number isintended. For example “C1-6 alkylenyl” or “C1-6 alkylene” denotesalkylenyl or alkylene having 1, 2, 3, 4, 5 or 6 carbon atoms. When thespecific number denoting the alkylenyl or alkylene group is the integer0 (zero), no alkylenyl or alkylene group having from 1 to 12 carbonatoms is present and instead a bond directly links the groups specifiedat each end of the alkylenyl or alkylene group. For example, “NH(COalkylene)NH₂” is equivalent to “NHNH₂” (hydrazino). As used herein, thegroups linked by an alkylene or alkylenyl group are intended to beattached to the first and to the last carbon of the alkylene oralkylenyl-group. As explained immediately above, when the alkylenyl oralkylene group is CO alkylenyl or CO alkylene, the group represents abond and the linked groups are thus directly linked to each other. Inthe case of methylene, the first and the last carbon is the same. Forexample, “H₂N(C2 alkylene)NH₂”, “H₂N(C3 alkylene)NH₂”, “N(C4 alkylene)”,“N(C5 alkylene)” and “N(C2 alkylene)₂NH” is equivalent to 1,2-diaminoethane, 1,3-diamino propane, pyrrolidinyl, piperidinyl and piperazinyl,respectively. Examples of alkylene or alkylenyl include, but are notlimited to, methylene, ethylene, propylene, and butylene.

As used herein, “alkoxy” or “alkyloxy” is intended to mean an alkylgroup as defined above with the indicated number of carbon atomsattached through an oxygen bridge. Examples of alkoxy include, but arenot limited to, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy,isobutoxy, t-butoxy, n-pentoxy, isopentoxy, cyclopropylmethoxy, allyloxyand propargyloxy. Similarly, “alkylthio” or “thioalkoxy” represent analkyl group as defined above with the indicated number of carbon atomsattached through a sulphur bridge.

As used herein, “fluoroalkyl”, “fluoroalkylene” and “fluoroalkoxy”, usedalone or as a suffix or prefix, refers to groups in which one, two, orthree of the hydrogen(s) attached to any of the carbons of thecorresponding alkyl, alkylene and alkoxy-groups are replaced by fluoro.

Examples of fluoroalkyl include, but are not limited to,trifluoromethyl, difluoromethyl, fluoromethyl, 2,2,2-trifluoroethyl,2-fluoroethyl and 3-fluoropropyl.

Examples of fluoroalkylene include, but are not limited to,difluoromethylene, fluoromethylene, 2,2-difluorobutylene and2,2,3-trifluorobutylene.

Examples of fluoroalkoxy include, but are not limited to,trifluoromethoxy, 2,2,2-trifluoroethoxy, 3,3,3-trifluoropropoxy and2,2-difluoropropoxy.

As used herein, “non-aromatic carbocycle”, whether alone or as a suffixor prefix, is intended to mean non-aromatic saturated and unsaturatedcarbomonocycles, having from 3 to 8 ring carbon atoms, such ascyclopropanyl, cyclopentanyl, cyclohexanyl, cyclopentenyl andcyclohexenyl. If a prefix, such as C3-C6, is given, when said carbocyclecomprises the indicated number of carbon atoms, eg. 3, 4, 5 or 6 carbonatoms. Accordingly, “C6 non-aromatic carbocycle” for example includescyclohexyl and cyclohexenyl. Non-aromatic unsaturated carbocycles are tobe distinguished from aryls, as aryl refers to aromatic ring structures,comprising at least one aromatic ring.

As used herein, “cycloalkyl”, whether alone or as a suffix or prefix, isintended to mean a saturated carbomonocycle, having from 3 to 8 ringcarbon atoms, such as cyclopropanyl, cyclopentanyl and cyclohexanyl. Ifa prefix, such as C3-C6, is given, when said cycloalkyl comprises theindicated number of carbon atoms, e.g. 3, 4, 5 or 6 carbon atoms.Accordingly, C6 cycloalkyl corresponds to cyclohexyl.

As used herein, “cycloalkenyl”, whether alone or as a suffix or prefix,is intended to mean a monounsaturated carbomonocycle, having from 4 to 8ring carbon atoms, such as cyclopentenyl and cyclohexenyl. If a prefix,such as C3-C6, is given, when said cycloalkenyl comprises the indicatednumber of carbon atoms, eg. 3, 4, 5 or 6 carbon atoms. Accordingly, C6cycloalkenyl corresponds to cyclohexenyl.

As used herein, the term “substitutable” refers to an atom to whichhydrogen may be covalently attached, and to which another substituentmay be present instead of the hydrogen. A non-limiting example ofsubstitutable atoms includes the carbon-atoms of pyridine. Thenitrogen-atom of pyridine is not substitutable according to thisdefinition. Further, according to the same definition, the iminenitrogen at position 3 in imidazole is not substitutable, while theamine nitrogen at position 1 is.

As used herein, the term “aryl” refers to a ring structure, comprisingat least one aromatic ring, made up of from 5 to 14 carbon atoms. Ringstructures containing 5, 6, or 7 carbon atoms would be single-ringaromatic groups, for example phenyl. Ring structures containing 8, 9,10, 11, 12, 13, or 14 carbon atoms would be polycyclic, for examplenaphthyl. The aromatic ring may be substituted at one or more ringpositions. The term “aryl” also includes polycyclic ring systems havingtwo or more cyclic rings in which two or more carbons are common to twoadjoining rings (the rings are “fused rings”) wherein at least one ofthe rings is aromatic, for example, the other cyclic rings may becycloalkyls, cycloalkenyls, cycloalkynyls, aryls and/or heterocyclyls.

The terms ortho, meta and para apply to 1,2-, 1,3- and 1,4-disubstitutedbenzenes, respectively. For example, the names 1,2-dimethylbenzene andortho-dimethylbenzene are synonymous.

As used herein, “heteroaryl” or “hetaryl” refers to an aromaticheterocycle, having at least one ring with aromatic character, (e.g. 6delocalized electrons) or at least two conjugated rings with aromaticcharacter, (e.g. 4n+2 delocalized electrons where “n” is an integer),and comprising up to about 14 carbon atoms, and having at least oneheteroatom ring member such as sulfur, oxygen, or nitrogen. Heteroarylor hetaryl groups include monocyclic and bicyclic (e.g., having 2 fusedrings) systems. The aromatic ring of the heteroaryl or hetaryl group maybe substituted at one or more ring positions.

Examples of heteroaryl or hetaryl groups include without limitation,pyridyl (i.e., pyridinyl), pyrimidinyl, pyrazinyl, pyridazinyl,triazinyl, furyl (i.e. furanyl), quinolyl, tetrahydroquinolyl,isoquinolyl, tetrahydroisoquinolyl, thienyl, imidazolyl, thiazolyl,indolyl, pyrryl, oxazolyl, benzofuryl, benzothienyl, benzthiazolyl,isoxazolyl, pyrazolyl, triazolyl, tetrazolyl, indazolyl,1,2,4-thiadiazolyl, isothiazolyl, benzothienyl, benzimidazolyl,indolinyl, and the like.

As used herein, “non-aromatic heterocycle” refers to a monocyclecomprising at least one heteroatom ring member, such as sulfur, oxygen,or nitrogen. Such monocyclic rings may be saturated or unsaturated.However, non-aromatic heterocycles are to be distinguished fromheteroaryl groups.

Examples of non-aromatic heterocycle groups include without limitationmorpholinyl, piperazinyl, 3H-diazirin-3-yl, oxiranyl, aziridinyl,piperidinyl, pyrrolidinyl, tetrahydrofuranyl, tetrahydropyranyl,dihydro-2H-pyranyl.

As used herein, the term “relative stereochemistry”, such as when e.g.referring to e.g. a drawing of a structure, is relating to the relativespatial arrangement of e.g. substituents or groups of a structure. Forexample, if the relative stereochemistry is indicated by drawingsubstituents or groups of a molecule in certain directions, thecorresponding mirror image of that molecule will have the same relativestereochemistry. On the other hand, if the “absolute stereochemistry” isindicated by drawing substituents or groups of a molecule in certaindirections, a particular enantiomer of that molecule is intended.

EMBODIMENTS OF THE INVENTION

Previously, galiellactone has only been administered intraperitoneally(ip) for in vivo studies. When the oral administration ofgaliellalactone (10 mg/kg) was investigated in mice, only very lowplasma levels of galiellalactone were achieved (C_(max)=52 ng/ml andAUC_(0-∞)=5.7 μg/mL·min). The data suggested that this was due to poorabsorption.

One way of increasing the bioavailability of a compound with low plasmaexposure is to make a prodrug of the active parent drug. The prodrug cane.g. increase the absorption after oral administration. After uptake theprodrug should preferably be converted to the active parent compoundeither through metabolism or spontaneous chemical reactions. One measureof improved drug like properties is the plasma exposure of the activeparent compound as measured over time (AUC).

Galiellalactone is a reactive Michael acceptor. From the literature itis known that reactive Michael acceptors can be converted to prodrugswith improved drug like properties by reacting them with differentamines to give amine-adducts (Woods et al Med. Chem. Commun., 2013, 4,27-33). This has for example been done with parthenolide (Neelakantan etal Bioorganic & Medicinal Chemistry Letters 19 (2009) 4346-4349) andarglabin. The amine-drug adducts are then converted in vivo to theactive parent compound.

Galiellalactone was therefore reacted with pyrrolidine to make anamine-galiellalactone adduct that could act as a potential prodrug.However, when dosed orally (10 mg/kg) in mice the plasma levels ofgaliellalactone were not improved at all compared to whengaliellalactone was dosed orally (cf. experimental parts below fordetails).

The chemical stability of the pyrrolidine-galiellalactone adduct wasinvestigated in 0.1 M PBS (pH 7.4) and it was found that it was veryunstable and it was found to be rapidly converted to galiellactone. Itwas envisaged that the lack of improved plasma exposure of the prodrugmight be due to its chemical instability. A series ofamine-galiellalactone adducts were evaluated for their chemicalstability, but all were found to be unstable in 0.1 M PBS (pH 7.4).

Also thiols, such as cysteine, may be used to convert Michael acceptorsto prodrugs. The addition of cysteine and cysteine Me-ester adducts ofgaliellalactone was confirmed to be reversible, thus also such adductsrepresents potential prodrug candidates. However, similarly to the amineadducts, the cysteine and cysteine Me-ester adducts of galiellalactonewere unstable in 0.1 M PBS (pH 7.4), thus precluding their use asprodrugs.

In order to provide a prodrug of galiellalactone, improving thebioavailability subsequent to oral administration, it was deemednecessary to provide chemically more stable adducts.

It was surprisingly found that the general low stability seen for amineadducts of galiellalactone is not seen among thiols adducts in general.Especially, it was found that use of N-acelyated cysteine Me-esterprovided a thiol adduct of galiellalactone being chemically stable in0.1 M PBS (pH 7.4; cf. experimental parts below for details).

N-acelyated cysteine Me-ester adduct of galiellalactone

Upon evaluation in vivo, the adduct was found to significantly improvethe plasma exposures of galiellalactone, compared to oral administrationof galiellalactone itself.

Further, it was found that also other thiol adducts had similarproperties. Without being bound to any theory, it seems that the aminogroup of the cysteine adduct provides means for intramolecularlyassisting a retro Michael attack releasing the Michael acceptor, i.e.galiellactone. Acylation, amidation, removal of the amino group (beta tothe sulfur atom of the cystein residue) all resulted in adducts withimproved stability and improved plasma exposures of galiellalactonecompared to oral administration of galiellalactone itself. Further,amino groups in other positions than beta to the sulfur atom of thecystein residue did seemingly not result in adducts being unstable inPBS. As an example, reacting the methyl ester of the di-peptide Val-Cyswith galiellactone resulted in a compound (cf. formula below) beingchemically stable in 0.1 M PBS.

Thus, an embodiment relates to a compound according to formula (I)

wherein

R₁ and R₁′ are independently selected from the group consisting of H,C1-5 alkyl, C1-5 fluoroalkyl, halo, C3-8 non-aromatic carbocycle, C0-5alkyleneOC0-5 alkyl, C0-3 alkyleneOC1-5 fluoroalkyl, C0-3alkyleneOC(O)C1-5 alkyl, OC2-3 alkyleneN(C0-5 alkyl)₂ in which the C0-5alkyl may be the same or different, C0-3 alkyleneNHC0-5 alkyl, C0-3alkyleneN(C1-5 alkyl)₂ in which the C1-5 alkyl may be the same ordifferent, C0-3 alkyleneN(C0-5 alkyl)C(O)C1-5 alkyl, C0-3alkyleneNHaryl, wherein the aryl is unsubstituted or substituted with aone or several substituents independently selected from the groupconsisting of C1-5 alkyl, C1-5 fluoroalkyl, halo, C0-5 alkyleneOC0-5alkyl, nitro, cyano and N(C0-5 alkyl)₂ in which the C0-5 alkyl may bethe same or different, C0-3 alkyleneNHheteroaryl, wherein saidheteroaryl is a 5- or 6-membered heteroaryl, said heteroaryl beingunsubstituted or substituted with a one or several independentlyselected C1-5 alkyl groups, C0-3 alkyleneC(O)NHC0-5 alkyl, C0-3alkyleneC(O)N(C1-5 alkyl)₂ in which the C1-5 alkyl may be the same ordifferent, C0-3 alkyleneC(O)N(C4-5 alkylene), C0-3 alkyleneC(O)OC0-5alkyl, a 3- to 8-membered non-aromatic heterocycle, C0-3 alkylene aryl,wherein the aryl is unsubstituted or substituted with a one or severalsubstituents independently selected from the group consisting of C1-5alkyl, C1-5 fluoroalkyl, halo, C0-5 alkyleneOC0-5 alkyl, nitro, cyanoand N(C0-5 alkyl)₂ in which the C0-5 alkyl may be the same or different,C0-3 alkylene heteroaryl, wherein said heteroaryl is a 5- or 6-memberedheteroaryl, said heteroaryl being unsubstituted or substituted with aone or several independently selected C1-5 alkyl groups, halo, C0-1alkylene cyano, SC0-5 alkyl, C0-3 alkyleneSO₂C0-5 alkyl, nitro,C(O)C0-C5 alkyl, C(O)C1-C5 fluoroalkyl, N(C0-C3 alkyl)SO₂C1-C5 alkyl,and N(C0-C5 alkyl)SO₂C1-5 fluoroalkyl;

R₂ and R₂′ are independently selected from the group consisting of H,C1-5 alkyl, C1-5 fluoroalkyl, halo, C3-8 non-aromatic carbocycle, C0-5alkyleneOC0-5 alkyl, C0-3 alkyleneOC1-5 fluoroalkyl, C0-3alkyleneOC(O)C1-5 alkyl, OC2-3 alkyleneN(C0-5 alkyl)₂ in which the C0-5alkyl may be the same or different, C0-3 alkyleneNHC0-5 alkyl, C0-3alkyleneN(C1-5 alkyl)₂ in which the C1-5 alkyl may be the same ordifferent, C0-3 alkyleneN(C0-5 alkyl)C(O)C1-5 alkyl, C0-3alkyleneNHaryl, wherein the aryl is unsubstituted or substituted with aone or several substituents independently selected from the groupconsisting of C1-5 alkyl, C1-5 fluoroalkyl, halo, C0-5 alkyleneOC0-5alkyl, nitro, cyano and N(C0-5 alkyl)₂ in which the C0-5 alkyl may bethe same or different, C0-3 alkyleneNHheteroaryl, wherein saidheteroaryl is a 5- or 6-membered heteroaryl, said heteroaryl beingunsubstituted or substituted with a one or several independentlyselected C1-5 alkyl groups, C0-3 alkyleneC(O)NHC0-5 alkyl, C0-3alkyleneC(O)N(C1-5 alkyl)₂ in which the C1-5 alkyl may be the same ordifferent, C0-3 alkyleneC(O)N(C4-5 alkylene), C0-3 alkyleneC(O)OC0-5alkyl, a 3- to 8-membered non-aromatic heterocycle, C0-3 alkylene aryl,wherein the aryl is unsubstituted or substituted with a one or severalsubstituents independently selected from the group consisting of C1-5alkyl, C1-5 fluoroalkyl, halo, C0-5 alkyleneOC0-5 alkyl, nitro, cyanoand N(C0-5 alkyl)₂ in which the C0-5 alkyl may be the same or different,C0-3 alkylene heteroaryl, wherein said heteroaryl is a 5- or 6-memberedheteroaryl, said heteroaryl being unsubstituted or substituted with aone or several independently selected C1-5 alkyl groups, halo, C0-1alkylene cyano, SC0-5 alkyl, C0-3 alkyleneSO₂C0-5 alkyl, nitro,C(O)C0-C5 alkyl, C(O)C1-C5 fluoroalkyl, N(C0-C3 alkyl)SO₂C1-C5 alkyl,and N(C0-C5 alkyl)SO₂C1-5 fluoroalkyl;

R₃ and R₃′ are independently selected from the group consisting of H,C1-5 alkyl, C1-5 fluoroalkyl, halo, C3-8 non-aromatic carbocycle, C0-5alkyleneOC0-5 alkyl, C0-3 alkyleneOC1-5 fluoroalkyl, C0-3alkyleneOC(O)C1-5 alkyl, OC2-3 alkyleneN(C0-5 alkyl)₂ in which the C0-5alkyl may be the same or different, C0-3 alkyleneNHC0-5 alkyl, C0-3alkyleneN(C1-5 alkyl)₂ in which the C1-5 alkyl may be the same ordifferent, C0-3 alkyleneN(C0-5 alkyl)C(O)C1-5 alkyl, C0-3alkyleneNHaryl, wherein the aryl is unsubstituted or substituted with aone or several substituents independently selected from the groupconsisting of C1-5 alkyl, C1-5 fluoroalkyl, halo, C0-5 alkyleneOC0-5alkyl, nitro, cyano and N(C0-5 alkyl)₂ in which the C0-5 alkyl may bethe same or different, C0-3 alkyleneNHheteroaryl, wherein saidheteroaryl is a 5- or 6-membered heteroaryl, said heteroaryl beingunsubstituted or substituted with a one or several independentlyselected C1-5 alkyl groups, C0-3 alkyleneC(O)NHC0-5 alkyl, C0-3alkyleneC(O)N(C1-5 alkyl)₂ in which the C1-5 alkyl may be the same ordifferent, C0-3 alkyleneC(O)N(C4-5 alkylene), C0-3 alkyleneC(O)OC0-5alkyl, a 3- to 8-membered non-aromatic heterocycle, C0-3 alkylene aryl,wherein the aryl is unsubstituted or substituted with a one or severalsubstituents independently selected from the group consisting of C1-5alkyl, C1-5 fluoroalkyl, halo, C0-5 alkyleneOC0-5 alkyl, nitro, cyanoand N(C0-5 alkyl)₂ in which the C0-5 alkyl may be the same or different,C0-3 alkylene heteroaryl, wherein said heteroaryl is a 5- or 6-memberedheteroaryl, said heteroaryl being unsubstituted or substituted with aone or several independently selected C1-5 alkyl groups, halo, C0-1alkylene cyano, SC0-5 alkyl, C0-3 alkyleneSO₂C0-5 alkyl, nitro,C(O)C0-C5 alkyl, C(O)C1-C5 fluoroalkyl, N(C0-C3 alkyl)SO₂C1-C5 alkyl,and N(C0-C5 alkyl)SO₂C1-5 fluoroalkyl;

R₄ and R₄′ are independently selected from the group consisting of H,C1-5 alkyl, C1-5 fluoroalkyl, halo, C3-8 non-aromatic carbocycle, C0-5alkyleneOC0-5 alkyl, C0-3 alkyleneOC1-5 fluoroalkyl, C0-3alkyleneOC(O)C1-5 alkyl, OC2-3 alkyleneN(C0-5 alkyl)₂ in which the C0-5alkyl may be the same or different, C0-3 alkyleneNHC0-5 alkyl, C0-3alkyleneN(C1-5 alkyl)₂ in which the C1-5 alkyl may be the same ordifferent, C0-3 alkyleneN(C0-5 alkyl)C(O)C1-5 alkyl, C0-3alkyleneNHaryl, wherein the aryl is unsubstituted or substituted with aone or several substituents independently selected from the groupconsisting of C1-5 alkyl, C1-5 fluoroalkyl, halo, C0-5 alkyleneOC0-5alkyl, nitro, cyano and N(C0-5 alkyl)₂ in which the C0-5 alkyl may bethe same or different, C0-3 alkyleneNHheteroaryl, wherein saidheteroaryl is a 5- or 6-membered heteroaryl, said heteroaryl beingunsubstituted or substituted with a one or several independentlyselected C1-5 alkyl groups, C0-3 alkyleneC(O)NHC0-5 alkyl, C0-3alkyleneC(O)N(C1-5 alkyl)₂ in which the C1-5 alkyl may be the same ordifferent, C0-3 alkyleneC(O)N(C4-5 alkylene), C0-3 alkyleneC(O)OC0-5alkyl, a 3- to 8-membered non-aromatic heterocycle, C0-3 alkylene aryl,wherein the aryl is unsubstituted or substituted with a one or severalsubstituents independently selected from the group consisting of C1-5alkyl, C1-5 fluoroalkyl, halo, C0-5 alkyleneOC0-5 alkyl, nitro, cyanoand N(C0-5 alkyl)₂ in which the C0-5 alkyl may be the same or different,C0-3 alkylene heteroaryl, wherein said heteroaryl is a 5- or 6-memberedheteroaryl, said heteroaryl being unsubstituted or substituted with aone or several independently selected C1-5 alkyl groups, halo, C0-1alkylene cyano, SC0-5 alkyl, C0-3 alkyleneSO₂C0-5 alkyl, nitro,C(O)C0-C5 alkyl, C(O)C1-C5 fluoroalkyl, N(C0-C3 alkyl)SO₂C1-C5 alkyl,and N(C0-C5 alkyl)SO₂C1-5 fluoroalkyl;

R₅ is selected from the group consisting of H, C1-5 alkyl, C1-5fluoroalkyl, C(O)C1-5 alkyl, C2-3 alkyleneN(C0-5 alkyl)₂ in which theC0-5 alkyl may be the same or different, C(O)N(0-5 alkyl)₂ in which theC0-5 alkyl may be the same or different, C(O)aryl, wherein the aryl isunsubstituted or substituted with a one or several substituentsindependently selected from the group consisting of C1-5 alkyl, C1-5fluoroalkyl, halo, C0-5 alkyleneOC0-5 alkyl, nitro, cyano and N(C0-5alkyl)₂ in which the C0-5 alkyl may be the same or different,C(O)heteroaryl, wherein said heteroaryl is a 5- or 6-memberedheteroaryl, said heteroaryl being unsubstituted or substituted with aone or several independently selected C1-5 alkyl groups,C(O)C1-C3alkylenearyl, wherein the aryl is unsubstituted or substitutedwith a one or several substituents independently selected from the groupconsisting of C1-5 alkyl, C1-5 fluoroalkyl, halo, C0-5 alkyleneOC0-5alkyl, nitro, cyano and N(C0-5 alkyl)₂ in which the C0-5 alkyl may bethe same or different, and C(O)C1-C3alkyleneheteroaryl, wherein saidheteroaryl is a 5- or 6-membered heteroaryl, said heteroaryl beingunsubstituted or substituted with a one or several independentlyselected C1-5 alkyl groups; and

R₆ is selected from the group consisting of H, C1-8 alkyl, C1-8fluoroalkyl, C3-C8 alkyleneN(C1-5 alkyl)₂ in which the C1-5 alkyl may bethe same or different, C2-5 alkyleneOC0-5 alkyl, C2-3 alkyleneOC1-5fluoroalkyl, C2-3 alkyleneOC(O)C1-5 alkyl, C3-5 alkyleneNHC0-5 alkyl,C2-3 alkyleneN(C0-5 alkyl)C(O)C1-5 alkyl, C2-5 alkyleneNHaryl, whereinthe aryl is unsubstituted or substituted with a one or severalsubstituents independently selected from the group consisting of C1-5alkyl, C1-5 fluoroalkyl, halo, C0-5 alkyleneOC0-5 alkyl, nitro, cyano,and N(C0-5 alkyl)₂ in which the C0-5 alkyl may be the same or different,C2-5 alkyleneNHheteroaryl, wherein said heteroaryl is a 5- or 6-memberedheteroaryl, said heteroaryl being unsubstituted or substituted with aone or several independently selected C1-5 alkyl groups, C1-3alkyleneC(O)NHC0-5 alkyl, C1-3 alkyleneC(O)N(C1-5 alkyl)₂ in which theC1-5 alkyl may be the same or different, C1-3 alkyleneC(O)N(C4-5alkylene), C1-3 alkyleneC(O)OC0-5 alkyl, a 3- to 8-membered non-aromaticheterocycle, C2-3 alkylene aryl, wherein the aryl is unsubstituted orsubstituted with a one or several substituents independently selectedfrom the group consisting of C1-5 alkyl, C1-5 fluoroalkyl, halo, C0-5alkyleneOC0-5 alkyl, nitro, cyano and N(C0-5 alkyl)₂ in which the C0-5alkyl may be the same or different, C1-3 alkylene heteroaryl, whereinsaid heteroaryl is a 5- or 6-membered heteroaryl, said heteroaryl beingunsubstituted or substituted with a one or several independentlyselected C1-5 alkyl groups, C1-3 alkyleneSO₂C0-5 alkyl, C1-5alkyleneSO₃H, aryl, wherein the aryl is unsubstituted or substitutedwith a one or several substituents independently selected from the groupconsisting of C1-5 alkyl, C1-5 fluoroalkyl, halo, C0-5 alkyleneOC0-5alkyl, nitro, cyano and N(C0-5 alkyl)₂ in which the C0-5 alkyl may bethe same or different, heteroaryl, wherein said heteroaryl is a 5- or6-membered heteroaryl, said heteroaryl being unsubstituted orsubstituted with a one or several independently selected C1-5 alkylgroups, and moieties according to formula (II),

wherein the waved line indicates the point of attachment to the sulfuratom in formula (I);

A is a C1-5 alkylene;

D is a bond, a phenylene, or a heteroarylene, wherein said heteroaryleneis a 5- or 6-membered heteroarylene;

E is a bond or a C1-5 alkylene;

X is NC0-C5 alkyl or “O” (oxygen);

R7 is selected from the group consisting of H, provided that X is NC0-C5alkyl, R7 is not to be H if X is “O” (oxygen), C1-C10 alkyl, C1-5alkyleneN(C1-5 alkyl)₂ in which the C1-5 alkyl may be the same ordifferent, C0-3 alkylene aryl, wherein the aryl is unsubstituted orsubstituted with a one or several substituents independently selectedfrom the group consisting of C1-5 alkyl, C1-5 fluoroalkyl, halo, C0-5alkyleneOC0-5 alkyl, nitro, cyano and N(C0-5 alkyl)₂ in which the C0-5alkyl may be the same or different, C1-3 alkylene heteroaryl, whereinsaid heteroaryl is a 5- or 6-membered heteroaryl, said heteroaryl beingunsubstituted or substituted with a one or several independentlyselected C1-5 alkyl groups, an amino acid residue selected from thegroup consisting alanine, arginine, asparagine, aspartic acid, cysteine,glutamine, glutamic acid, glycine, histidine, isoleucine, leucine,lysine; methionine, phenylalanine, proline, threonine, tryptophan,tyrosine and valine, which amino acid residue is connected to the moietyaccording to formula (II) at the N-terminal of the amino acid residueand optionally esterfied at the C-terminal with a C1-5 monohydricalkanol, and a di-, a tri-, or a tetrapeptide residue, wherein the aminoacid residues in said peptide residue are independently selected fromthe group consisting alanine, arginine, asparagine, aspartic acid,cysteine, glutamine, glutamic acid, glycine, histidine, isoleucine,leucine, lysine; methionine, phenylalanine, proline, threonine,tryptophan, tyrosine and valine, the peptide residue being connected tothe moiety according to formula (II) at the N-terminal of the peptideand optionally esterfied at the C-terminal with a C1-5 monohydricalkanol; and

R8 is selected from the group consisting of C(O)C1-C6 alkyl, C(O)OC1-C6alkyl, C(O)C0-3 alkylene aryl, wherein the aryl is unsubstituted orsubstituted with a one or several substituents independently selectedfrom the group consisting of C1-5 alkyl, C1-5 fluoroalkyl, halo, C0-5alkyleneOC0-5 alkyl, nitro, cyano and N(C0-5 alkyl)₂ in which the C0-5alkyl may be the same or different, C(O)C0-3 alkylene heteroaryl,wherein said heteroaryl is a 5- or 6-membered heteroaryl, saidheteroaryl being unsubstituted or substituted with a one or severalindependently selected C1-5 alkyl groups, an amino acid residue selectedfrom the group consisting alanine, arginine, asparagine, aspartic acid,cysteine, glutamine, glutamic acid, glycine, histidine, isoleucine,leucine, lysine; methionine, phenylalanine, proline, threonine,tryptophan, tyrosine and valine, which amino acid residue is connectedto the moiety according to formula (II) at the C-terminal of the aminoacid residue, and which amino acid residue optionally is N-acylated,wherein said acyl group is selected from the group consisting C(O)C1-C6alkyl, and C(O)C0-3 alkylene aryl, wherein the aryl is unsubstituted orsubstituted with a one or several substituents independently selectedfrom the group consisting of C1-5 alkyl, C1-5 fluoroalkyl, halo, C0-5alkyleneOC0-5 alkyl, nitro, cyano and N(C0-5 alkyl)₂ in which the C0-5alkyl may be the same or different, and a di-, a tri-, or a tetrapeptideresidue, wherein the amino acid residues in said peptide residue areindependently selected from the group consisting alanine, arginine,asparagine, aspartic acid, cysteine, glutamine, glutamic acid, glycine,histidine, isoleucine, leucine, lysine; methionine, phenylalanine,proline, threonine, tryptophan, tyrosine and valine, the peptide residuebeing connected to the moiety according to formula (II) at theC-terminal of the peptide, and the N-terminal of the peptide optionallybeing N-acelyated, wherein said acyl group is selected from the groupconsisting C(O)C1-C6 alkyl and C(O)C0-3 alkylene aryl, wherein the arylis unsubstituted or substituted with a one or several substituentsindependently selected from the group consisting of C1-5 alkyl, C1-5fluoroalkyl, halo, C0-5 alkyleneOC0-5 alkyl, nitro, cyano and N(C0-5alkyl)₂ in which the C0-5 alkyl may be the same or different;

as a free base, an acid in its non-charged protonated form, apharmaceutically acceptable addition salt, solvate, solvate of a saltthereof, a pure diastereomer, a pure enantiomer, a diastereomericmixture, a racemic mixture, a scalemic mixture, a correspondingtautomeric form resulting from a hydrogen shift between two hetero-atomsand/or the corresponding tautomeric form resulting from a keto-enoltautomerization.

In compounds wherein R6 is moiety according to formula (II) and “D”represents a bond, “A” is directly connected to “E”. Similarly, incompounds wherein R₆ is moiety according to formula (II) and “E”represents a bond, “D” is directly connected to the sulfur atom offormula (I). In compounds wherein R6 is moiety according to formula (II)and both D″ and “E” represent a bond, “A” is directly connected to thesulfur atom of formula (I) (cf. formula (IV) further below).

The individual diastereomers or enantiomers in a diastereomeric orscalemic mixture, respectively, may be present in the same amount, thusconstituting a racemic mixture in the latter case, or in differentamounts. However, it is preferred if one of the diastereomers orenantiomers prevails. Accordingly, its is preferred if one of thediastereomers or enantiomers is more than 50%, such as more than 75%,90%, 95% or even more than 99%.

According to an embodiment, the compounds of the formula (I) have therelative or absolute stereochemistry according to formula (III),

Compounds having the absolute stereochemistry according to formula (III)may be obtained by use of the natural product galiellalactone. Anembodiment thus relates to compounds of the formula (I) having theabsolute stereochemistry according to formula (III).

Preferably, C3-8 non-aromatic carbocycles of compounds herein areindependently selected from the group consisting of cyclohexyl,cyclopentyl and cyclopropyl. Further, any heteroaryl of compounds hereinare independently selected among 5-membered heteroaryls, such asthiazolyl, furanyl, thiophenyl, pyrrolyl, pyrazolyl, oxazolyl orisooxazolyl, and 6-membered heteroaryls, such as pyridyl or pyrimidinyl.In addition, 3- to 8-membered non-aromatic heterocycles of compoundsherein are preferably and independently selected from the groupconsisting of piperidinyl, piperazinyl, morpholinyl or pyrrolidinyl.Preferably, these heterocycles are connected via a substitutablenitrogen atom. Additionally, aryls of compounds herein are preferablyand independently selected among phenyl groups and naphtalenyl. Whensubstituted, heteroaryl(s) of compounds herein are substituted atsubstitutable atom(s).

Preferably, any halo is fluoro, chloro or bromo.

According to an embodiment, R₁, R₁′, R₂, R₂′ R₃, R₃′, R₄ and R₄′ of acompound of formula (I) are independently selected from the groupconsisting of H, C1-5 alkyl, C0-5 alkyleneOC0-5 alkyl, C0-3alkyleneNHC0-5 alkyl, C0-3 alkyleneN(C1-5 alkyl)2 in which the C1-5alkyl may be the same or different, C0-3 alkyleneN(C0-5 alkyl)C(O)C1-5alkyl, C0-3 alkyleneC(O)N(C1-5 alkyl)2 in which the C1-5 alkyl may bethe same or different, C0-3 alkyleneC(O)OC0-5 alkyl, a 3- to 8-memberednon-aromatic heterocycle, C0-3 alkylene aryl, wherein the aryl isunsubstituted or substituted with a one or several substituentsindependently selected from the group consisting of C1-5 alkyl, C1-5fluoroalkyl, halo, C0-5 alkyleneOC0-5 alkyl, nitro, cyano and N(C0-5alkyl)₂ in which the C0-5 alkyl may be the same or different, and C0-3alkylene heteroaryl. In such an embodiment, R₁ may be C1-5 alkyl, suchas methyl, and R₁′, R₂, R₂′ R₃, R₃′, R₄ and R₄′ may be independentlyselected from the group consisting of H, C1-5 alkyl, C0-5 alkyleneOC0-5alkyl, C0-3 alkyleneNHC0-5 alkyl, C0-3 alkyleneN(C1-5 alkyl)2 in whichthe C1-5 alkyl may be the same or different, C0-3 alkyleneN(C0-5alkyl)C(O)C1-5 alkyl, C0-3 alkyleneC(O)N(C1-5 alkyl)2 in which the C1-5alkyl may be the same or different, C0-3 alkyleneC(O)OC0-5 alkyl, a 3-to 8-membered non-aromatic heterocycle, C0-3 alkylene aryl, wherein thearyl is unsubstituted or substituted with a one or several substituentsindependently selected from the group consisting of C1-5 alkyl, C1-5fluoroalkyl, halo, C0-5 alkyleneOC0-5 alkyl, nitro, cyano and N(C0-5alkyl)₂ in which the C0-5 alkyl may be the same or different, and C0-3alkylene heteroaryl. Further, according to such an embodiment, R₁ may beC1-5 alkyl, such as methyl, R₁′, R₂, R₂′ R₃, R₃′, and R₄′ may all be H,and R₄ may be selected from the group consisting of H, C1-5 alkyl, C0-5alkyleneOC0-5 alkyl, C0-3 alkyleneNHC0-5 alkyl, C0-3 alkyleneN(C1-5alkyl)2 in which the C1-5 alkyl may be the same or different, C0-3alkyleneN(C0-5 alkyl)C(O)C1-5 alkyl, C0-3 alkyleneC(O)N(C1-5 alkyl)2 inwhich the C1-5 alkyl may be the same or different, C0-3alkyleneC(O)OC0-5 alkyl, a 3- to 8-membered non-aromatic heterocycle,C0-3 alkylene aryl, wherein the aryl is unsubstituted or substitutedwith a one or several substituents independently selected from the groupconsisting of C1-5 alkyl, C1-5 fluoroalkyl, halo, C0-5 alkyleneOC0-5alkyl, nitro, cyano and N(C0-5 alkyl)₂ in which the C0-5 alkyl may bethe same or different, and C0-3 alkylene heteroaryl. Further, R₅ of acompound of formula (I) may be selected from H, C1-5 alkyl, and C(O)C1-5alkyl. Accordingly, R₅ may be H, Me, or C(O)C1-5 alkyl, such as R₅ beingH.

According to an embodiment, R₁, R₁′, R₂, R₂′, R₃, R₃′, R₄ and R₄′ of acompound of formula (I) are independently selected from the groupconsisting of H, C1-5 alkyl, halo, aryl, wherein the aryl isunsubstituted or substituted with a one or several substituentsindependently selected from the group consisting of C1-5 alkyl, C1-5fluoroalkyl, halo, C0-5 alkyleneOC0-5 alkyl, nitro, cyano and N(C0-5alkyl)₂ in which the C0-5 alkyl may be the same or different, CH₂aryl,wherein the aryl is unsubstituted or substituted with a one or severalsubstituents independently selected from the group consisting of C1-5alkyl, C1-5 fluoroalkyl, halo, C0-5 alkyleneOC0-5 alkyl, nitro, cyanoand N(C0-5 alkyl)₂ in which the C0-5 alkyl may be the same or different,heteroaryl, wherein said heteroaryl is a 5- or 6-membered heteroaryl,said heteroaryl being unsubstituted or substituted with a one or severalindependently selected C1-5 alkyl groups, and CH₂heteroaryl, whereinsaid heteroaryl is a 5- or 6-membered heteroaryl, said heteroaryl beingunsubstituted or substituted with a one or several independentlyselected C1-5 alkyl groups.

In some embodiments of the compound of formula (I), R₁ is halo; R₁′ ismethyl; R₂, R₂′, R₃, and R₃′ are all hydrogen; R₄ and R₄′ areindependently selected from the group consisting of H and phenyl; and R₅preferably is H. In these embodiments, R₁ may be fluorine. Further, inthese embodiments, R₄ may be H or phenyl; and R₄′ is hydrogen;preferably also R₄ is H.

According to an embodiment, R₁, R₁′, R₂, R₂′ R₃, R₃′, R₄ and R₄′ of acompound of formula (I) are independently selected from the groupconsisting of H, C1-5 alkyl, aryl, wherein the aryl is unsubstituted orsubstituted with a one or several substituents independently selectedfrom the group consisting of C1-5 alkyl, C1-5 fluoroalkyl, halo, C0-5alkyleneOC0-5 alkyl, nitro, cyano and N(C0-5 alkyl)₂ in which the C0-5alkyl may be the same or different, CH₂aryl, wherein the aryl isunsubstituted or substituted with a one or several substituentsindependently selected from the group consisting of C1-5 alkyl, C1-5fluoroalkyl, halo, C0-5 alkyleneOC0-5 alkyl, nitro, cyano and N(C0-5alkyl)₂ in which the C0-5 alkyl may be the same or different, heteroaryland CH₂heteroaryl. In such an embodiment, R₁ may be C1-5 alkyl, such asmethyl, and R₁′, R₂, R₂′ R₃, R₃′, R₄ and R₄′ may be independentlyselected from the group consisting of H, C1-5 alkyl, aryl, wherein thearyl is unsubstituted or substituted with a one or several substituentsindependently selected from the group consisting of C1-5 alkyl, C1-5fluoroalkyl, halo, C0-5 alkyleneOC0-5 alkyl, nitro, cyano and N(C0-5alkyl)₂ in which the C0-5 alkyl may be the same or different, CH₂aryl,wherein the aryl is unsubstituted or substituted with a one or severalsubstituents independently selected from the group consisting of C1-5alkyl, C1-5 fluoroalkyl, halo, C0-5 alkyleneOC0-5 alkyl, nitro, cyanoand N(C0-5 alkyl)₂ in which the C0-5 alkyl may be the same or different,heteroaryl and CH₂heteroaryl. Further, according to such an embodiment,R₁ may be C1-5 alkyl, such as methyl, R₁′, R₂, R₂′ R₃, R₃′, and R₄′ mayall be H, and R₄ may be selected from the group consisting of H, C1-5alkyl, aryl, wherein the aryl is unsubstituted or substituted with a oneor several substituents independently selected from the group consistingof C1-5 alkyl, C1-5 fluoroalkyl, halo, C0-5 alkyleneOC0-5 alkyl, nitro,cyano and N(C0-5 alkyl)₂ in which the C0-5 alkyl may be the same ordifferent, CH₂aryl, wherein the aryl is unsubstituted or substitutedwith a one or several substituents independently selected from the groupconsisting of C1-5 alkyl, C1-5 fluoroalkyl, halo, C0-5 alkyleneOC0-5alkyl, nitro, cyano and N(C0-5 alkyl)₂ in which the C0-5 alkyl may bethe same or different, heteroaryl and CH2heteroaryl. In addition, R5 ofa compound of formula (I) may be selected from H and C1-5 alkyl.Preferably, R5 is H.

According to an embodiment, R₁ is C1-5 alkyl, such as methyl, R₁′, R₂,R₂′, R₃, and R₃′ are all H, or R₁ is halo, such as fluorine, R₁′ is C1-5alkyl, such as methyl, R₂, R₂′, R₃, and R₃′ are all H, and R₄ and R₄′are independently selected from the group consisting of H, C1-5 alkyl,aryl, wherein the aryl is unsubstituted or substituted with a one orseveral substituents independently selected from the group consisting ofC1-5 alkyl, C1-5 fluoroalkyl, halo, C0-5 alkyleneOC0-5 alkyl, nitro,cyano and N(C0-5 alkyl)₂ in which the C0-5 alkyl may be the same ordifferent, and CH₂aryl, wherein the aryl is unsubstituted or substitutedwith a one or several substituents independently selected from the groupconsisting of C1-5 alkyl, C1-5 fluoroalkyl, halo, C0-5 alkyleneOC0-5alkyl, nitro, cyano and N(C0-5 alkyl)₂ in which the C0-5 alkyl may bethe same or different. Preferably, also R₄′ is hydrogen in such anembodiment.

According to an embodiment, R₂, R₂′, R₃ and R₃′ of a compound of formula(I) are all H. Also R₄ and R₄′ of a compound of formula (I) may both beH. Further, one of R₄ and R₄′ may be methyl, the other being H.

According to an embodiment, R₅ of a compound of formula (I) may be H.

According to an embodiment, at least one of R₁′, R₂, R₂′, R₃ and R₃′,such as 1, 2, 3 or all 4 of R₂, R₂′, R₃ and R₃′, of a compound offormula (I) is H. Further, According to an embodiment, R₁′, R₂, R₂′, R₃,R₃′, R₄ and R₄′ of a compound of formula (I) are all H. Further, R₁ maybe methyl or hydrogen, such as being methyl.

According to an embodiment at least one of R₂, R₂′, R₃ and R₃′, such as1, 2, 3 or all 4 of R₂, R₂′, R₃ and R₃′, of a compound of formula (I) ishydrogen. Further, also R₄ and R₄′ of a compound of formula (I) may behydrogen. In such an embodiment, R₁ and R₁′ may be selected from thegroup consisting of fluorine, methyl, and hydrogen. In an embodimentwherein R₂, R₂′, R₃, R₃′, R₄ and R₄′ of a compound of formula (I) allare hydrogen, R₁ may be fluorine and R₁′ methyl, or R₁ may be methyl andR₁′ hydrogen.

According to an embodiment, at least one of R₁, R₁′, R₂, R₂′, R₃, R₃′,R₄ and R₄′ of a compound disclosed herein may be independently selectedfrom the group consisting of C1-5 alkyl, aryl, wherein the aryl isunsubstituted or substituted with a one or several substituentsindependently selected from the group consisting of C1-5 alkyl, C1-5fluoroalkyl, halo, C0-5 alkyleneOC0-5 alkyl, nitro, cyano and N(C0-5alkyl)₂ in which the C0-5 alkyl may be the same or different, CH₂aryl,wherein the aryl is unsubstituted or substituted with a one or severalsubstituents independently selected from the group consisting of C1-5alkyl, C1-5 fluoroalkyl, halo, C0-5 alkyleneOC0-5 alkyl, nitro, cyanoand N(C0-5 alkyl)₂ in which the C0-5 alkyl may be the same or different,heteroaryl and CH₂heteroaryl. Especially, in a compound of formula (I),wherein at least one of R₁, R₁′, R₂, R₂′, R₃, R₃′, R₄ and R₄′ in acompound of formula (I) is C1-5 alkyl, aryl, wherein the aryl isunsubstituted or substituted with a one or several substituentsindependently selected from the group consisting of C1-5 alkyl, C1-5fluoroalkyl, halo, C0-5 alkyleneOC0-5 alkyl, nitro, cyano and N(C0-5alkyl)₂ in which the C0-5 alkyl may be the same or different, CH₂aryl,wherein the aryl is unsubstituted or substituted with a one or severalsubstituents independently selected from the group consisting of C1-5alkyl, C1-5 fluoroalkyl, halo, C0-5 alkyleneOC0-5 alkyl, nitro, cyanoand N(C0-5 alkyl)₂ in which the C0-5 alkyl may be the same or different,heteroaryl or CH₂heteroaryl, at least one of R₂, R₂′, R₃, R₃′, R₄ andR₄′ of a compound disclosed herein may be independently selected fromthe group consisting of C1-5 alkyl, aryl, wherein the aryl isunsubstituted or substituted with a one or several substituentsindependently selected from the group consisting of C1-5 alkyl, C1-5fluoroalkyl, halo, C0-5 alkyleneOC0-5 alkyl, nitro, cyano and N(C0-5alkyl)₂ in which the C0-5 alkyl may be the same or different, CH₂aryl,wherein the aryl is unsubstituted or substituted with a one or severalsubstituents independently selected from the group consisting of C1-5alkyl, C1-5 fluoroalkyl, halo, C0-5 alkyleneOC0-5 alkyl, nitro, cyanoand N(C0-5 alkyl)₂ in which the C0-5 alkyl may be the same or different,heteroaryl and CH₂heteroaryl. Further, in a compound of formula (I),wherein at least one of R₂, R₂′, R₃, R₃′, R₄ and R₄′ in a compound offormula (I) is C1-5 alkyl, aryl, wherein the aryl is unsubstituted orsubstituted with a one or several substituents independently selectedfrom the group consisting of C1-5 alkyl, C1-5 fluoroalkyl, halo, C0-5alkyleneOC0-5 alkyl, nitro, cyano and N(C0-5 alkyl)₂ in which the C0-5alkyl may be the same or different, CH₂aryl, wherein the aryl isunsubstituted or substituted with a one or several substituentsindependently selected from the group consisting of C1-5 alkyl, C1-5fluoroalkyl, halo, C0-5 alkyleneOC0-5 alkyl, nitro, cyano and N(C0-5alkyl)₂ in which the C0-5 alkyl may be the same or different, heteroarylor CH₂heteroaryl, at least one of R₃, R₃′, R₄ and R₄′ of a compounddisclosed herein may be independently selected from the group consistingof C1-5 alkyl, aryl, wherein the aryl is unsubstituted or substitutedwith a one or several substituents independently selected from the groupconsisting of C1-5 alkyl, C1-5 fluoroalkyl, halo, C0-5 alkyleneOC0-5alkyl, nitro, cyano and N(C0-5 alkyl)₂ in which the C0-5 alkyl may bethe same or different, CH₂aryl, wherein the aryl is unsubstituted orsubstituted with a one or several substituents independently selectedfrom the group consisting of C1-5 alkyl, C1-5 fluoroalkyl, halo, C0-5alkyleneOC0-5 alkyl, nitro, cyano and N(C0-5 alkyl)₂ in which the C0-5alkyl may be the same or different, heteroaryl and CH₂heteroaryl.Furthermore, in a compound of formula (I), wherein at least one of R₃,R₃′, R₄ and R₄′ in a compound of formula (I) is C1-5 alkyl, aryl,wherein the aryl is unsubstituted or substituted with a one or severalsubstituents independently selected from the group consisting of C1-5alkyl, C1-5 fluoroalkyl, halo, C0-5 alkyleneOC0-5 alkyl, nitro, cyanoand N(C0-5 alkyl)₂ in which the C0-5 alkyl may be the same or different,CH₂aryl, wherein the aryl is unsubstituted or substituted with a one orseveral substituents independently selected from the group consisting ofC1-5 alkyl, C1-5 fluoroalkyl, halo, C0-5 alkyleneOC0-5 alkyl, nitro,cyano and N(C0-5 alkyl)₂ in which the C0-5 alkyl may be the same ordifferent, heteroaryl or CH₂heteroaryl, at least one of R₄ and R₄′, suchas R₄, of a compound disclosed herein may be independently selected fromthe group consisting of C1-5 alkyl, aryl, wherein the aryl isunsubstituted or substituted with a one or several substituentsindependently selected from the group consisting of C1-5 alkyl, C1-5fluoroalkyl, halo, C0-5 alkyleneOC0-5 alkyl, nitro, cyano and N(C0-5alkyl)₂ in which the C0-5 alkyl may be the same or different, CH₂aryl,wherein the aryl is unsubstituted or substituted with a one or severalsubstituents independently selected from the group consisting of C1-5alkyl, C1-5 fluoroalkyl, halo, C0-5 alkyleneOC0-5 alkyl, nitro, cyanoand N(C0-5 alkyl)₂ in which the C0-5 alkyl may be the same or different,heteroaryl and CH2heteroaryl. Especially, R4 may be aryl, wherein thearyl is unsubstituted or substituted with a one or several substituentsindependently selected from the group consisting of C1-5 alkyl, C1-5fluoroalkyl, halo, C0-5 alkyleneOC0-5 alkyl, nitro, cyano and N(C0-5alkyl)₂ in which the C0-5 alkyl may be the same or different, orCH₂aryl, such as being phenyl.

According to an embodiment, at least one of R₁ and R₁′ of a compounddisclosed herein is independently selected from the group consisting ofC1-5 alkyl, such as methyl, aryl, such as phenyl, CH₂aryl, such asbenzyl, heteroaryl and CH₂heteroaryl. Thus, at least one of R₁ and R₁′may be C1-5 alkyl, such as methyl. Preferably, R₁ is methyl in such anembodiment. Alternatively, R₁ is fluorine and R₁′ is methyl.

According to an embodiment, R₁ and R₁′ of a compound disclosed hereinare independently selected from the group consisting of H, halo, andmethyl. While both R₁ and R₁′ may both be H, it's preferred for one ofR₁ and R₁′ to be methyl, the other one being H or fluorine. Preferably,R1 is methyl and R1′ is H. Alternatively, R₁ may fluorine and R₁′methyl.

According to an embodiment, R₁ is methyl, R₁′ is hydrogen, R₂, R₂′, R₃,and R₃′ are all hydrogen, and R₄ and R₄′ are independently selected fromthe group consisting of H and phenyl. Further, in such an embodiment,also R₄′ may be hydrogen. Compounds wherein also R₄ is hydrogen may beobtained from galiellalactone. Thus, also R₄ may be hydrogen. Ingaliellalactone R₅ is H. Thus, it may be preferred if R₅ is H. However,the tertiary hydroxyl group may be modified, such as by alkylation andacylation.

According to an embodiment, R₁ is fluorine, R₁′ is methyl, R₂, R₂′, R₃,and R₃′ are all hydrogen, and R₄ and R₄′ are independently selected fromthe group consisting of H and phenyl. Further, in such an embodiment,also R₄′ may be hydrogen. Compounds wherein also R₄ is hydrogen may beobtained from galiellalactone. Thus, also R₄ may be hydrogen. Ingaliellalactone R₅ is H. Thus, it may be preferred if R₅ is H. However,the tertiary hydroxyl group may be modified, such as by alkylation andacylation. Compounds wherein R₂, R₂′, R₃, R₃′, R₄, R₄′, and R₅ all arehydrogen, R₁ is fluorine, and R₁′ is methyl may be obtained fromgaliellalactone.

An embodiment relates to compounds disclosed herein, wherein R₆ isselected from the group consisting of C1-8 alkyl, C3-C8 alkyleneN(C1-5alkyl)₂ in which the C1-5 alkyl may be the same or different, C2-5alkyleneOC0-5 alkyl, C1-3 alkyleneC(O)OC0-5 alkyl, a 3- to 8-memberednon-aromatic heterocycle, C2-3 alkylene aryl, wherein the aryl isunsubstituted or substituted with a one or several substituentsindependently selected from the group consisting of C1-5 alkyl, C1-5fluoroalkyl, halo, C0-5 alkyleneOC0-5 alkyl, nitro, cyano and N(C0-5alkyl)₂ in which the C0-5 alkyl may be the same or different, C1-5alkyleneSO3, aryl, wherein the aryl is unsubstituted or substituted witha one or several substituents independently selected from the groupconsisting of C1-5 alkyl, C1-5 fluoroalkyl, halo, C0-5 alkyleneOC0-5alkyl, nitro, cyano and N(C0-5 alkyl)₂ in which the C0-5 alkyl may bethe same or different, heteroaryl, wherein said heteroaryl is a 5- or6-membered heteroaryl, said heteroaryl being unsubstituted orsubstituted with a one or several independently selected C1-5 alkylgroups, and moieties according to formula (II). When R₆ is a moietyaccording to formula (II):

“D” may be a bond or a phenylene, further may “E” be a bond;

R₇ may be selected from the group consisting of H, provided that X isNC0-C5 alkyl, R₇ is not to be H if X is “O” (oxygen), C1-C10 alkyl, suchas methyl, and C0-3 alkylene aryl, such as phenyl and benzyl. The arylmay be unsubstituted or substituted with a one or several substituentsindependently selected from the group consisting of C1-5 alkyl, C1-5fluoroalkyl, halo, C0-5 alkyleneOC0-5 alkyl, nitro, cyano and N(C0-5alkyl)₂ in which the C0-5 alkyl may be the same or different; and

R₈ may be selected from the group consisting of C(O)C1-C6 alkyl, such asC(O)Me, C(O)C0-3 alkylene aryl, such as C(O)Ph, wherein the aryl isunsubstituted or substituted with a one or several substituentsindependently selected from the group consisting of C1-5 alkyl, C1-5fluoroalkyl, halo, C0-5 alkyleneOC0-5 alkyl, nitro, cyano and N(C0-5alkyl)₂ in which the C0-5 alkyl may be the same or different, and anamino acid residue selected from the group consisting alanine, glycine,isoleucine, leucine, lysine, methionine, phenylalanine, tyrosine andvaline, which amino acid residue is connected to the moiety according toformula (II) at the C-terminal of the amino acid residue.

Moieties according to formula (II), wherein R₈ is an amino acid residue,may be represented by the following formula:

wherein R represents the substituent of the amino acid.

An embodiment relates to compounds disclosed herein, wherein —SR₆comprises a cysteine residue, or an analogue to a cysteine residue, suchas a homocysteine residue. In such an embodiment R₆ is a moietyaccording to formula (IV),

wherein the waved line indicates the point of attachment to the sulfuratom in formula (I);

A is a C1-5 alkylene, such as methylene or ethylene;

R₉ corresponds to R₈ in formula (I); and

R₁₀ corresponds to R₇ in formula (I).

In embodiment, wherein R₆ is a moiety according to formula (IV), R₉ maybe selected from the group consisting of C(O)C1-C6 alkyl, such asC(O)Me, C(O)C0-3 alkylene aryl, such as C(O)phenyl or C(O)benzyl,wherein the aryl is unsubstituted or substituted with a one or severalsubstituents independently selected from the group consisting of C1-5alkyl, C1-5 fluoroalkyl, halo, C0-5 alkyleneOC0-5 alkyl, nitro, cyanoand N(C0-5 alkyl)₂ in which the C0-5 alkyl may be the same or different,and an amino acid residue selected from the group consisting alanine,glycine, isoleucine, leucine, lysine; methionine, phenylalanine,tyrosine and valine, which amino acid residue is connected to the moietyaccording to formula (IV) at the C-terminal of the amino acid residue,and R₁₀ may be selected from the group consisting of C1-C10 alkyl, suchas methyl, and C0-3 alkylene aryl, such as phenyl or benzyl, wherein thearyl is unsubstituted or substituted with a one or several substituentsindependently selected from the group consisting of C1-5 alkyl, C1-5fluoroalkyl, halo, C0-5 alkyleneOC0-5 alkyl, nitro, cyano and N(C0-5alkyl)₂ in which the C0-5 alkyl may be the same or different. Inembodiment, wherein R₆ is a moiety according to formula (IV), R₉ may beC(O)Me.

Compounds disclosed herein may be obtained by reacting a cysteinederivative with a galiellalactone. An embodiment, thus relates to acompound according to formula (V),

wherein R₉ corresponds to R₈ in formula (I) and R₁₀ corresponds to R₇ informula (I). Further, R₉ may be selected from the group consisting ofC(O)C1-C5 alkyl, such as methyl, C(O)C0-3 alkylene aryl, such asC(O)phenyl, wherein the aryl is unsubstituted or substituted with a oneor several substituents independently selected from the group consistingof fluorine, chlorine and bromine, and an amino acid residue selectedfrom the group consisting alanine, glycine, isoleucine, leucine, lysineand valine, which amino acid residue is connected to the moietyaccording to formula (IV) at the C-terminal of the amino acid residue.Further, R₁₀ may be selected from the group consisting of C1-C6 alkyland C0-3 alkylene aryl, such as phenyl or benzyl, wherein the aryl isunsubstituted or substituted with a one or several substituentsindependently selected from the group consisting of fluorine, chlorineand bromine.

According to an embodiment, the compound of formula (I) is selected fromthe group consisting of

as a mixture of diastereomers, a pure diastereomer, a racemic mixture, ascalemic mixture or a pure enantiomer. Preferably, the compound is aracemic mixture or, more preferred, a pure enantiomer with the aboveindicated absolute stereochemistry.

According to an embodiment, the compound of formula (I) is selected fromthe group consisting of

as a mixture of diastereomers, a pure diastereomer, a racemic mixture, ascalemic mixture or a pure enantiomer. Preferably, the compound is aracemic mixture or, more preferred, a pure enantiomer with the aboveindicated absolute stereochemistry.

According to another aspect, there is provided a compound of formula(Ia)

wherein

R₁ is halo;

R₁′ is selected from the group consisting of H, C1-5 alkyl, C1-5fluoroalkyl, halo, C3-8 non-aromatic carbocycle, C0-5 alkyleneOC0-5alkyl, C0-3 alkyleneOC1-5 fluoroalkyl, C0-3 alkyleneOC(O)C1-5 alkyl,OC2-3 alkyleneN(C0-5 alkyl)₂ in which the C0-5 alkyl may be the same ordifferent, C0-3 alkyleneNHC0-5 alkyl, C0-3 alkyleneN(C1-5 alkyl)₂ inwhich the C1-5 alkyl may be the same or different, C0-3 alkyleneN(C0-5alkyl)C(O)C1-5 alkyl, C0-3 alkyleneNHaryl, wherein the aryl isunsubstituted or substituted with a one or several substituentsindependently selected from the group consisting of C1-5 alkyl, C1-5fluoroalkyl, halo, C0-5 alkyleneOC0-5 alkyl, nitro, cyano and N(C0-5alkyl)₂ in which the C0-5 alkyl may be the same or different, C0-3alkyleneNHheteroaryl, wherein said heteroaryl is a 5- or 6-memberedheteroaryl, said heteroaryl being unsubstituted or substituted with aone or several independently selected C1-5 alkyl groups, C0-3alkyleneC(O)NHC0-5 alkyl, C0-3 alkyleneC(O)N(C1-5 alkyl)₂ in which theC1-5 alkyl may be the same or different, C0-3 alkyleneC(O)N(C4-5alkylene), C0-3 alkyleneC(O)OC0-5 alkyl, a 3- to 8-membered non-aromaticheterocycle, C0-3 alkylene aryl, wherein the aryl is unsubstituted orsubstituted with a one or several substituents independently selectedfrom the group consisting of C1-5 alkyl, C1-5 fluoroalkyl, halo, C0-5alkyleneOC0-5 alkyl, nitro, cyano and N(C0-5 alkyl)₂ in which the C0-5alkyl may be the same or different, C0-3 alkylene heteroaryl, whereinsaid heteroaryl is a 5- or 6-membered heteroaryl, said heteroaryl beingunsubstituted or substituted with a one or several independentlyselected C1-5 alkyl groups, halo, C0-1 alkylene cyano, SC0-5 alkyl, C0-3alkyleneSO₂C0-5 alkyl, nitro, C(O)C0-C5 alkyl, C(O)C1-C5 fluoroalkyl,N(C0-C3 alkyl)SO₂C1-C5 alkyl, and N(C0-C5 alkyl)SO₂C1-5 fluoroalkyl;

R₂ and R₂′ are independently selected from the group consisting of H,C1-5 alkyl, C1-5 fluoroalkyl, halo, C3-8 non-aromatic carbocycle, C0-5alkyleneOC0-5 alkyl, C0-3 alkyleneOC1-5 fluoroalkyl, C0-3alkyleneOC(O)C1-5 alkyl, OC2-3 alkyleneN(C0-5 alkyl)₂ in which the C0-5alkyl may be the same or different, C0-3 alkyleneNHC0-5 alkyl, C0-3alkyleneN(C1-5 alkyl)₂ in which the C1-5 alkyl may be the same ordifferent, C0-3 alkyleneN(C0-5 alkyl)C(O)C1-5 alkyl, C0-3alkyleneNHaryl, wherein the aryl is unsubstituted or substituted with aone or several substituents independently selected from the groupconsisting of C1-5 alkyl, C1-5 fluoroalkyl, halo, C0-5 alkyleneOC0-5alkyl, nitro, cyano and N(C0-5 alkyl)₂ in which the C0-5 alkyl may bethe same or different, C0-3 alkyleneNHheteroaryl, wherein saidheteroaryl is a 5- or 6-membered heteroaryl, said heteroaryl beingunsubstituted or substituted with a one or several independentlyselected C1-5 alkyl groups, C0-3 alkyleneC(O)NHC0-5 alkyl, C0-3alkyleneC(O)N(C1-5 alkyl)₂ in which the C1-5 alkyl may be the same ordifferent, C0-3 alkyleneC(O)N(C4-5 alkylene), C0-3 alkyleneC(O)OC0-5alkyl, a 3- to 8-membered non-aromatic heterocycle, C0-3 alkylene aryl,wherein the aryl is unsubstituted or substituted with a one or severalsubstituents independently selected from the group consisting of C1-5alkyl, C1-5 fluoroalkyl, halo, C0-5 alkyleneOC0-5 alkyl, nitro, cyanoand N(C0-5 alkyl)₂ in which the C0-5 alkyl may be the same or different,C0-3 alkylene heteroaryl, wherein said heteroaryl is a 5- or 6-memberedheteroaryl, said heteroaryl being unsubstituted or substituted with aone or several independently selected C1-5 alkyl groups, halo, C0-1alkylene cyano, SC0-5 alkyl, C0-3 alkyleneSO₂C0-5 alkyl, nitro,C(O)C0-C5 alkyl, C(O)C1-C5 fluoroalkyl, N(C0-C3 alkyl)SO₂C1-C5 alkyl,and N(C0-C5 alkyl)SO₂C1-5 fluoroalkyl;

R₃ and R₃′ are independently selected from the group consisting of H,C1-5 alkyl, C1-5 fluoroalkyl, halo, C3-8 non-aromatic carbocycle, C0-5alkyleneOC0-5 alkyl, C0-3 alkyleneOC1-5 fluoroalkyl, C0-3alkyleneOC(O)C1-5 alkyl, OC2-3 alkyleneN(C0-5 alkyl)₂ in which the C0-5alkyl may be the same or different, C0-3 alkyleneNHC0-5 alkyl, C0-3alkyleneN(C1-5 alkyl)₂ in which the C1-5 alkyl may be the same ordifferent, C0-3 alkyleneN(C0-5 alkyl)C(O)C1-5 alkyl, C0-3alkyleneNHaryl, wherein the aryl is unsubstituted or substituted with aone or several substituents independently selected from the groupconsisting of C1-5 alkyl, C1-5 fluoroalkyl, halo, C0-5 alkyleneOC0-5alkyl, nitro, cyano and N(C0-5 alkyl)₂ in which the C0-5 alkyl may bethe same or different, C0-3 alkyleneNHheteroaryl, wherein saidheteroaryl is a 5- or 6-membered heteroaryl, said heteroaryl beingunsubstituted or substituted with a one or several independentlyselected C1-5 alkyl groups, C0-3 alkyleneC(O)NHC0-5 alkyl, C0-3alkyleneC(O)N(C1-5 alkyl)₂ in which the C1-5 alkyl may be the same ordifferent, C0-3 alkyleneC(O)N(C4-5 alkylene), C0-3 alkyleneC(O)OC0-5alkyl, a 3- to 8-membered non-aromatic heterocycle, C0-3 alkylene aryl,wherein the aryl is unsubstituted or substituted with a one or severalsubstituents independently selected from the group consisting of C1-5alkyl, C1-5 fluoroalkyl, halo, C0-5 alkyleneOC0-5 alkyl, nitro, cyanoand N(C0-5 alkyl)₂ in which the C0-5 alkyl may be the same or different,C0-3 alkylene heteroaryl, wherein said heteroaryl is a 5- or 6-memberedheteroaryl, said heteroaryl being unsubstituted or substituted with aone or several independently selected C1-5 alkyl groups, halo, C0-1alkylene cyano, SC0-5 alkyl, C0-3 alkyleneSO₂C0-5 alkyl, nitro,C(O)C0-C5 alkyl, C(O)C1-C5 fluoroalkyl, N(C0-C3 alkyl)SO₂C1-C5 alkyl,and N(C0-C5 alkyl)SO₂C1-5 fluoroalkyl; and

R₄ and R₄′ are independently selected from the group consisting of H,C1-5 alkyl, C1-5 fluoroalkyl, halo, C3-8 non-aromatic carbocycle, C0-5alkyleneOC0-5 alkyl, C0-3 alkyleneOC1-5 fluoroalkyl, C0-3alkyleneOC(O)C1-5 alkyl, OC2-3 alkyleneN(C0-5 alkyl)₂ in which the C0-5alkyl may be the same or different, C0-3 alkyleneNHC0-5 alkyl, C0-3alkyleneN(C1-5 alkyl)₂ in which the C1-5 alkyl may be the same ordifferent, C0-3 alkyleneN(C0-5 alkyl)C(O)C1-5 alkyl, C0-3alkyleneNHaryl, wherein the aryl is unsubstituted or substituted with aone or several substituents independently selected from the groupconsisting of C1-5 alkyl, C1-5 fluoroalkyl, halo, C0-5 alkyleneOC0-5alkyl, nitro, cyano and N(C0-5 alkyl)₂ in which the C0-5 alkyl may bethe same or different, C0-3 alkyleneNHheteroaryl, wherein saidheteroaryl is a 5- or 6-membered heteroaryl, said heteroaryl beingunsubstituted or substituted with a one or several independentlyselected C1-5 alkyl groups, C0-3 alkyleneC(O)NHC0-5 alkyl, C0-3alkyleneC(O)N(C1-5 alkyl)₂ in which the C1-5 alkyl may be the same ordifferent, C0-3 alkyleneC(O)N(C4-5 alkylene), C0-3 alkyleneC(O)OC0-5alkyl, a 3- to 8-membered non-aromatic heterocycle, C0-3 alkylene aryl,wherein the aryl is unsubstituted or substituted with a one or severalsubstituents independently selected from the group consisting of C1-5alkyl, C1-5 fluoroalkyl, halo, C0-5 alkyleneOC0-5 alkyl, nitro, cyanoand N(C0-5 alkyl)₂ in which the C0-5 alkyl may be the same or different,C0-3 alkylene heteroaryl, wherein said heteroaryl is a 5- or 6-memberedheteroaryl, said heteroaryl being unsubstituted or substituted with aone or several independently selected C1-5 alkyl groups, halo, C0-1alkylene cyano, SC0-5 alkyl, C0-3 alkyleneSO₂C0-5 alkyl, nitro,C(O)C0-C5 alkyl, C(O)C1-C5 fluoroalkyl, N(C0-C3 alkyl)SO₂C1-C5 alkyl,and N(C0-C5 alkyl)SO₂C1-5 fluoroalkyl;

as a free base, an acid in its non-charged protonated form, apharmaceutically acceptable addition salt, solvate, solvate of a saltthereof, a pure diastereomer, a pure enantiomer, a diastereomericmixture, a racemic mixture, a scalemic mixture, a correspondingtautomeric form resulting from a hydrogen shift between two hetero-atomsand/or the corresponding tautomeric form resulting from a keto-enoltautomerization.

According to an embodiment, the compound of the formula (Ia) has therelative or absolute stereochemistry according to formula (Ma)

According to some embodiments of the compounds of formula (Ia) or (Ma),R₁′, R₂, R₂′, R₃, R₃′, R₄ and R₄′ are independently selected from thegroup consisting of H, C1-5 alkyl, halo, aryl, wherein the aryl isunsubstituted or substituted with a one or several substituentsindependently selected from the group consisting of C1-5 alkyl, C1-5fluoroalkyl, halo, C0-5 alkyleneOC0-5 alkyl, nitro, cyano and N(C0-5alkyl)₂ in which the C0-5 alkyl may be the same or different, CH₂aryl,wherein the aryl is unsubstituted or substituted with a one or severalsubstituents independently selected from the group consisting of C1-5alkyl, C1-5 fluoroalkyl, halo, C0-5 alkyleneOC0-5 alkyl, nitro, cyanoand N(C0-5 alkyl)₂ in which the C0-5 alkyl may be the same or different,heteroaryl, wherein said heteroaryl is a 5- or 6-membered heteroaryl,said heteroaryl being unsubstituted or substituted with a one or severalindependently selected C1-5 alkyl groups, and CH₂heteroaryl, whereinsaid heteroaryl is a 5- or 6-membered heteroaryl, said heteroaryl beingunsubstituted or substituted with a one or several independentlyselected C1-5 alkyl groups.

In some embodiments of the compounds of formula (Ia) or (Ma), R₁ isfluorine.

According to some embodiments of the compounds of formula (Ia) or (Ma),R₁′ is selected from the group consisting of H, C1-5 alkyl, C1-5fluoroalkyl, halo, aryl, CH2aryl, heteroaryl and CH2heteroaryl.

In one embodiment of the compounds of formula (Ia) or (Ma), R₁′ is C1-5alkyl. In this embodiment, R₁′ may be methyl.

According to some embodiments of the compounds of formula (Ia) or (Ma),R₂, R₂′, R₃, R₃′, R₄ and R₄′ are independently selected from the groupconsisting of H, C1-5 alkyl, aryl, CH₂aryl, heteroaryl andCH₂heteroaryl.

In some embodiments of the compounds of formula (Ia) or (Ma), R₂, R₂′,R₃, R₃′, R₄ and R₄′ are all H.

In one particular embodiment of the compounds of formula (Ia), R₁ isfluorine; R₁′ is methyl; and R₂, R₂′, R₃, R₃′, R₄, and R₄′ are all H.

According to an embodiment, the compound of formula (Ia) is

According to another aspect, there is provided a pharmaceuticalcomposition comprising a compound according to formula (Ia) and at leastone pharmaceutically acceptable carrier or excipient. Such compound offormula (Ia) and composition are useful in therapy.

According to another aspect, compounds according to formula (Ia) andcompositions comprising such compounds are useful in the treatment ofSTAT3 signaling related disorders as well as in treatment of diseasesand disorders selected from the group consisting of: solid cancers,hematological cancers, benign tumors, hyperproliferative diseases,inflammations, autoimmune diseases, graft or transplant rejections,delayed physiological function of grafts or transplants,neurodegenerative diseases and viral infections, such as from solidcancers and hematological cancers.

Without wishing to be bound by theory it is believed that including oneor more halogen atoms, such as fluorine, in the tricyclic ring core ofthe compounds of formula (I) or (Ia) may increase the metabolicstability of the compound thus making it more resistant to metabolicdegradation and resulting in a more desirable pharmacokinetic profile ofthe compound.

According to an embodiment, a compound of formula (I) or (Ia) may be ina crystalline form. For example, such a crystalline form may facilitatethe manufacturing of a medicament comprising a compound of formula (I)or (Ia).

Although various selections, within the interval given for each of thedifferent groups of formula (I) or (Ia), have been describedindividually above as various possible embodiments, any combination ofthese selections is also possible and thus within the scope of thepresent invention. Accordingly, other embodiments of the inventionrelates to a compound according to formula (I) or (Ia), wherein at leasttwo different groups, such as 2, 3, 4, 5, or further different groups,of formula (I) or (Ia) are to be selected from the various selections,within the interval given for each of the different groups of formula(I) or (Ia), disclosed herein.

Compositions

Compounds disclosed herein, e.g. compounds according to formula (I) or(Ia) or preferred selections thereof, may be formulated intoconventional pharmaceutical compositions, e.g. medicaments. According toan embodiment, there is thus provided a pharmaceutical compositioncomprising a compound as disclosed herein and at least onepharmaceutically acceptable carrier or excipient. In this context“pharmaceutically acceptable” is intended to mean an excipient orcarrier that, at the dosage and concentrations employed, does not causeany unwanted effects in the patients to whom it is administered. Suchpharmaceutically acceptable carriers and excipients are well-known inthe art. Further, pharmaceutical composition, as described herein, mayalso comprise pharmaceutically diluents, stabilizers and the like.

The pharmaceutically acceptable carriers may be either solid or liquid.

Pharmaceutical compositions may typically be provided either as solid oras liquid preparations.

Solid form preparations include, but are not limited to, powders,tablets, dispersible granules, capsules, cachets, and suppositories.Powders, tablets, dispersible granules, capsules, cachets may be used assolid dosage forms suitable for oral administration, while suppositoriesmay be used for rectal administration.

A solid carrier may be one or more substances, which may also act asdiluent, flavoring agent, solubilizer, lubricant, suspending agent,binder, or tablet disintegrating agent. A solid carrier may also be anencapsulating material. Suitable carriers include, but are not limitedto, magnesium carbonate, magnesium stearate, talc, lactose, sugar,pectin, dextrin, starch, tragacanth, methyl cellulose, sodiumcarboxymethyl cellulose, low-melting wax, cocoa butter, and the like.

In powders, the carrier is normally a finely divided solid, which is ina mixture with the compound as disclosed herein, also typically beingfinely divided. In tablets, the active component may be mixed with thecarrier having the necessary binding properties in suitable proportionsand compacted in the shape and size desired.

For preparing suppository compositions, a low-melting wax, such as amixture of fatty acid glycerides and cocoa butter, may first be meltedand the active ingredient, like a compound of the invention, may then bedispersed therein by, for example, stirring. The molten homogeneousmixture may then be poured into convenient sized moulds and allowed tocool and solidify.

The term composition is also intended to include the formulation of theactive component with encapsulating material as a carrier providing acapsule in which the active component (with or without other carriers)is surrounded by a carrier which is thus in association with it.Similarly, cachets are included.

Liquid form preparations include, but are not limited to, solutions,suspensions, and emulsions. For example, dissolvation or dispersion ofthe compounds disclosed herein in sterile water or mixture of water andpropylene glycol may provide liquid preparations suitable for parenteraladministration. Liquid compositions may also be formulated in solutionin aqueous polyethylene glycol solution.

Aqueous solutions for oral administration may be prepared by dissolvingthe active component, like a compound of the invention, in water andadding suitable colorants, flavoring agents, stabilizers, and thickeningagents as desired. Aqueous suspensions for oral use may be made bydispersing the finely divided active component in water together with aviscous material such as natural synthetic gums, resins, methylcellulose, sodium carboxymethyl cellulose, and other suspending agentsknown to the pharmaceutical formulation art. Exemplary compositionsintended for oral use may contain one or more coloring, sweetening,flavoring and/or preservative agents.

A pharmaceutical composition according to embodiments disclosed hereinmay be administered through different routes such as, but not limitedto, intravenously, intraperitonealy, intramuscularly, intranasaly,subcutaneously, sublingually, rectally, orally as well as throughinhalation or insufflation.

Depending on the mode of administration, the pharmaceutical compositionmay include from about 0.05 wt % (percent by weight) to about 99 wt %,such as about 0.10 wt % to about 50 wt %, about 0.5 wt % to about 30, orabout 1.0 wt % to about 25 wt %, of a compound disclosed herein, allpercentages by weight being based on the total weight of thecomposition.

Therapy

Compounds disclosed herein, e.g. compounds according to formula (I) or(Ia) or preferred selections thereof, as well as pharmaceuticalcompositions comprising such a compounds, may be used for the treatmentof various diseases or conditions in humans or mammals, such as dogs,cats, horses, cows or other mammals; in particular domestic mammals.Mammals may be treated for the same diseases and conditions as humansmay be treated for.

When used in therapy, a pharmaceutical composition according embodimentsherein may be administered to the patient in a pharmaceuticallyeffective dose. By “pharmaceutically effective dose” is meant a dosethat is sufficient to produce the desired effects in relation to thecondition for which it is administered. The exact dose may be dependenton the activity of the compound, manner of administration, nature andseverity of the disorder and/or disease and the general conditions, suchas age and body weight of the patient.

A therapeutically effective amount for the practice of the presentinvention may be determined by one of ordinary skill in the art usingknown criteria including the age, weight and response of the individualpatient, and interpreted within the context of the disease which isbeing treated or which is being prevented.

Treatment of STAT3 Signaling Related Disorder and Inhibition ofProliferation of Cancer Cells

The parent compound galiellalactone and related compounds (cf. WO2012/010555) are covalent inhibitors of STAT3, binding directly to STAT3and preventing DNA binding. As described herein above, the transcriptionfactor STAT3 has emerged as a highly promising target for the treatmentof various cancers, e.g. castration resistant prostate cancer (CRPC). InCRPC, constitutive activation of STAT3 is implicated in drug resistance,the progression of androgen independent growth, metastasis, immuneavoidance and tumor growth.

Galiellalactone has indeed been found to inhibit proliferation of DU145prostate cancer cells (cf. Hellsten et al; Prostate 68; 269-280, 2008).Without being bound to any theory, it is believed that Galiellalactoneinduces apoptosis by down regulating STAT3 related genes.

As the compounds disclosed herein are rapidly absorbed and converted tothe parent compound, being a Michael acceptor, e.g. galiellalactone,when administered orally, they may be used to treatment or prevention ofa STAT3 signaling related disorder. Further, independently if exertedvia their effect on STAT3 signaling or not, compounds disclosed hereinmay be used in the treatment of cancer, as they inhibit proliferation ofcancer cells.

An embodiment thus relates to compounds and pharmaceutical compositionsdisclosed herein, e.g. compounds according to formula (I) or (Ia) orpreferred selections thereof, for use in treatment or prevention of aSTAT3 signaling related disorder. Examples of STAT3 signaling relateddisorders include various cancers, such as solid cancers andhematological cancer, benign tumors, hyperproliferative diseases,inflammation, autoimmune diseases, graft or transplant rejections,delayed physiological function of grafts or transplants,neurodegenerative diseases or viral infections.

In addition to the effect on STAT3, galiellalactone has also been shownto block TGF-beta signaling (Rudolph et al Cytokine. 2013 January;61(1):285-96) and to be effective in an in vivo murine model of allergicasthma (Hausding et al Int Immunol. 2011 January; 23(1):1-15).

Irrespectively of interfering with STAT3 signaling or not, compounds andpharmaceutical compositions disclosed herein may be used in thetreatment or prevention of cancer. Another embodiment thus relates tocompounds and pharmaceutical compositions disclosed herein for use inthe prevention or treatment of cancer, such as solid cancers orhematological cancers.

Examples of solid cancers include, but are not limited to, sarcomas,breast cancer, prostate cancer, head and neck cancer, brain tumors,colorectal cancer, lung cancer, pancreatic cancer, cervical cancer,ovarian cancer, melanoma, gastric cancers, renal cell carcinoma,endometrial cancer, sarcomas and hepatocellular carcinomas. Exampleshematological cancers include, but are not limited to, chronicmyelogenous leukemia, acute myelogenous leukemia, cutaneous T-celllymphoma, Hodgkin's disease, anaplastic large-cell lymphoma andBurkitt's lymphoma.

Further, the cancers to be treated by compounds and pharmaceuticalcompositions disclosed herein, are according to an embodiment selectedfrom the group consisting of leukemia, lymphomas, multiple myeloma,breast cancer, prostate carcinoma, lung cancer (non-small-cell), renalcell carcinoma lung cancer, hepatocellular carcinoma,cholangiocarcinoma, ovarian carcinoma, pancreatic adenocarcinoma,melanoma, head and neck squamous cell carcinoma.

Irrespectively if interfering with STAT3 signaling or not, compounds andpharmaceutical compositions disclosed herein may be used in thetreatment or prevention of benign tumors. Another embodiment thusrelates to compounds and pharmaceutical compositions disclosed hereinfor use in the prevention or treatment of benign tumors, including forexample Cardiac myxoma and Castleman's disease.

Compounds and pharmaceutical compositions disclosed herein may inhibitproliferation or angiogenesis, induces apoptosis, sensitizes toapoptosis or causes cytotoxicity of cancer cells, including cancer stemcells e.g. leukemic, prostate and breast cancer stem cells. Preferably,the cancer displays elevated or aberrant STAT3 signaling or activity,constitutively phosphorylated or active STAT3 or increased STAT3 proteinexpression. According to an embodiment, compounds and pharmaceuticalcompositions disclosed herein are thus used to inhibit the growth ormigration of cells. These cells may have elevated or aberrant STAT3signaling or activity, constitutively phosporylated or active STAT3 orincreased STAT3 protein expression. Hence, associated diseases anddisorders, such as hyperproliferative diseases, may be treated orprevented by use of compounds and pharmaceutical compositions disclosedherein. Another embodiment thus relates to compounds and pharmaceuticalcompositions disclosed herein for use in the prevention or treatmenthyperproliferative diseases.

IL-6 often is often involved in STAT3 signaling. Independently ofinvolving effects or not of STAT3 signaling, compounds andpharmaceutical compositions disclosed herein may be used for treatmentor prevention of IL-6 mediated inflammation and/or autoimmune diseasesand disorders, such as diseases and disorders related to the productionof acute phase proteins. Another embodiment thus relates to compoundsand pharmaceutical compositions disclosed herein for use in theprevention or treatment of IL-6 mediated inflammation and/or autoimmunediseases and disorders. Such diseases and disorders include, but are notlimited to, atherosclerosis, diabetes type 2, dementia, osteoporosis,hypertension, coronary artery disease.

According to an embodiment, compounds and pharmaceutical compositionsdisclosed herein are used for the prevention or treatment ofinflammatory and/or autoimmune diseases including, but not limited to,arthritis, Crohn's disease, ulcerative colitis, rheumatoid arthritis,inflammatory bowel diseases, asthma, allergy, e.g. Atopic dermatitis,systemic lupus erythematosus, uveitis and COPD. In addition, compoundsof the invention may be used for the suppression of graft and transplantrejection, or for improved onset of the physiological functions of suchgrafts and transplants after transplantation.

According to an embodiment, compounds and pharmaceutical compositionsdisclosed herein are used for the prevention or treatment ofinflammatory, autoimmune and neurodegenerative diseases affecting theCNS including, but not limited to, Parkinson's disease, Alzheimer'sdisease, multiple sclerosis, stroke and ischemia reperfusion injury.

According to an embodiment, compounds and pharmaceutical compositionsdisclosed herein are used for the prevention or treatment of chronicviral infections including, but not limited to, hepatitis C, herpes,infections caused by Kaposis Sarcoma-associated herpes virus (KSHV) andEpstein-Barr virus related infections.

According to an embodiment, compounds and pharmaceutical compositionsdisclosed herein are prevention or treatment of hyperproliferativediseases including, but not limited to, psoriasis.

When used in therapy, a pharmaceutical composition according embodimentsherein may be administered to the patient in a pharmaceuticallyeffective dose. By “pharmaceutically effective dose” is meant a dosethat is sufficient to produce the desired effects in relation to thecondition for which it is administered. The dose required for thetherapeutic or preventive treatment of a particular disease or disorderwill necessarily be varied depending on the host treated, the route ofadministration and the severity of the illness being treated. Further,the exact dose may be dependent on the activity of the compound, mannerof administration, nature and severity of the disorder and/or diseaseand the general conditions, such as age and body weight of the patient.

A therapeutically effective amount for the practice of the presentinvention may be determined by one of ordinary skill in the art usingknown criteria including the age, weight and response of the individualpatient, and interpreted within the context of the disease which isbeing treated or which is being prevented.

Evidently, compounds and pharmaceutical compositions disclosed hereinmay used for the manufacture of a medicament for use in such treatmentand prevention as disclosed herein.

Similarly, compounds and compositions disclosed herein may obviouslyalso be used in method for treating or preventing such diseases anddisorders as have been disclosed herein. Such a method includes the stepof administering an effective amount of the compound, or thepharmaceutical composition, to a subject in need for such treatment.

In the context of the present specification, the term “therapy” and“treatment” includes prevention or prophylaxis, unless there arespecific indications to the contrary. The terms “therapeutic” and“therapeutically” should be construed accordingly.

According to an embodiment, treatment does also encompass pre-treatment,i.e. prophylactic treatment.

When used herein, “prevent/preventing” should not be construed to meanthat a condition and/or a disease never might occur again after use of acompound or pharmaceutical composition according to embodimentsdisclosed herein to achieve prevention. Further, the term should neitherbe construed to mean that a condition not might occur, at least to someextent, after such use to prevent said condition. Rather,“prevent/preventing” is intended to mean that the condition to beprevented, if occurring despite such use, will be less severe thanwithout such use.

Combination Therapy

As already described, pharmaceutical composition as disclosed herein maybe used in therapy, the disclosed compounds, e.g. compounds according toformula I or preferred selections thereof, acting as the principaltherapeutic agent.

However, the disclosed compound may also be supplemented with additionaltherapeutically active agent(s). According to an embodiment, thepharmaceutical composition does comprise one or more additionaltherapeutic agent(s). Preferably, the one or more additional therapeuticagents are selected among therapeutic agents having a mechanism ofaction that differ from the mechanism of action of the compounddisclosed herein. An advantageous synergistic effect between thetherapeutic agent and the compound disclosed herein may then occur,allowing a more effective combat of e.g. a disease than if only such atherapeutic agent or a compound as disclosed herein is used. Theadditional therapeutic agent may be an anti-cancer agent, e.g.chemotherapeutic agents. Further, also other therapeutic agents wellknown in the art, being effective for other diseases and conditions asdescribed herein, may advantageously be used in combination with acompound as disclosed herein, in order to e.g. achieve a synergisticeffect.

According to an embodiment, a compound or a pharmaceutical compositionas disclosed herein is used in combination with other treatments ortherapies, in particular cancer therapies, including chemotherapy,radiation therapy, gene therapy, cell therapy and surgery. As anexample, compounds disclosed herein may enhance anti-tumor immunemediated cytotoxicity. Hence, synergistic effects between a compounddisclosed herein, and another treatment or therapy or an immune mediatedresponse, may favorably occur.

According to an embodiment, a pharmaceutical composition according toembodiments herein may be administered alone or in combination withother therapeutic agents. These agents may be incorporated as part ofthe same pharmaceutical composition or may be administered separately.It is well known in the art that a combination of mechanisticallyunrelated therapeutic agents in the same medicament may have beneficialeffects in the treatment of conditions or diseases characterized by e.g.abnormal immune regulation, abnormal hematopoiesis, inflammation oroncogenesis.

Examples of other therapeutic agents include, but is not limited to,anti-cancer agents such as Abraxane, Abiraterone, Aldesleukin,Alemtuzumab, Aminolevulinic Acid, Anastrozole, Aprepitant, ArsenicTrioxide, Azacitidine, Bendamustine Hydrochloride, Bevacizumab,Bexarotene, Bortezomib, Bleomycin, Cabazitaxel, Capecitabine,Carboplatin, Cetuximab, Cisplatin, Clofarabine, Cyclophosphamide,Cytarabine, Dacarbazine, Dasatinib, Daunorubicin Hydrochloride,Decitabine, Degarelix, Denileukin Diftitox, Dexrazoxane Hydrochloride,Docetaxel, Doxorubicin Hydrochloride, Doxorubicin HydrochlorideLiposome, Eltrombopag Olamine, Enzalutamide, Epirubicin Hydrochloride,Erlotinib Hydrochloride, Etoposide, Etoposide Phosphate, Everolimus,Exemestane, Filgrastim, Fludarabine Phosphate, Fluorouracil,Fulvestrant, Gefitinib, Gemcitabine Hydrochloride, Ibritumomab Tiuxetan,Imatinib Mesylate, Imiquimod, Irinotecan Hydrochloride, Ixabepilone,Lapatinib Ditosylate, Lenalidomide, Letrozole, Leucovorin Calcium,Leuprolide Acetate, Liposomal Cytarabine, Methotrexate, Nelarabine,Nilotinib, Ofatumumab, Oxaliplatin, Paclitaxel, Palifermin, PalonosetronHydrochloride, Panitumumab, Pazopanib Hydrochloride, Pegaspargase,Pemetrexed Disodium, Plerixafor, Pralatrexate, Raloxifene Hydrochloride,Rasburicase, Recombinant HPV Bivalent Vaccine, Recombinant HPVQuadrivalent Vaccine, Rituximab, Romidepsin, Romiplostim, Sipuleucel-T,Sorafenib Tosylate, Sunitinib Malate, Talc, Tamoxifen Citrate,Tasquinimod, TAK700, Temozolomide, Temsirolimus, Thalidomide, TopotecanHydrochloride, Toremifene, Tositumomab and I 131 Iodine Tositumomab,Trastuzumab, Vincristine Sulfate, Vorinostat, ARN-509, ODM-201,custirsen, AT 101, cisplatin, abozantinib, dasatinib, MK2206, axitinib,saracatinib, tivantinib, linsitinib, GSK2636771, BKM120, Vorinostat,panobinostat, azacitidine, IPI-504, STA9090, lenalidomid, OGX-427,Zoledronic Acid and Xofigo, or the like.

When a compound according to embodiments disclosed herein is combinedwith at least another therapeutic agent, such as an anti-cancer agent,in a pharmaceutical composition, such as a medicament, a therapeuticallyeffective dose of the pharmaceutical composition may comprise 1 to 10times less than the respective established therapeutically effectivedose of a component, i.e. a compound according to the invention or thetherapeutic agent, when administered alone for prevention or treatmentof the same disease or condition.

Accordingly, by combining a compound according to embodiments disclosedherein with another therapeutic agent, such as an anti-cancer agent, itmay be possible to achieve synergistic effects compared to if only acompound according to the present invention, or the other therapeuticagent, were administrated alone.

For example compounds as disclosed herein, e.g. compounds according toformula I, may be used for reversing drug resistance and/or enhancingeffects of anti cancer agents, thus offering the possibility of loweringthe dose of the anticancer agent to avoid side-effects and/or enhancingthe efficacy.

Pharmacological Tools

According to an embodiment, compounds disclosed herein are useful aspharmacological tools in the development and standardization of in-vitroand in-vivo test systems for the evaluation of other compounds withsimilar activity. Such in-vivo test systems include tests in laboratoryanimals such as cats, dogs, rabbits, monkeys, pigs, goats, guinea pigs,rats and mice. Furthermore, compounds disclosed herein may be used asmolecular probes to identify and/or locate the target of their action,such as targets of relevance for STAT3 signaling, as well as employed asa diagnostic tool for diagnosis of a disease or condition in-vivo,ex-vivo or in-vitro, or as synthetic precursors to such probes.

Molecular probes are based on compounds disclosed herein, wherein one orseveral of the composing atoms have been enriched with a radioactive orby other means detectable isotope, and fluorescent compounds as wellknown to the one skilled in the art. Hence, compounds disclosed hereinmay include compounds wherein one or several atoms have been substitutedwith heavier isotopes, such as substitution of hydrogen for deuterium,carbon-12 for carbon-13 or carbon-14, and/or nitrogen-14 fornitrogen-15.

Although the present invention has been described above with referenceto specific illustrative embodiments, it is not intended to be limitedto the specific form set forth herein. Any combination of the abovementioned embodiments should be appreciated as being within the scope ofthe invention. Rather, the invention is limited only by the accompanyingclaims and other embodiments than the specific above are equallypossible within the scope of these appended claims.

In the claims, the term “comprises/comprising” does not exclude thepresence of other species or steps. Additionally, although individualfeatures may be included in different claims, these may possiblyadvantageously be combined, and the inclusion in different claims doesnot imply that a combination of features is not feasible and/oradvantageous. In addition, singular references do not exclude aplurality. The terms “a”, “an”, “first”, “second” etc do not preclude aplurality

Methods of Preparation

Another embodiment relates to a process for preparing a compounddisclosed herein, e.g. compounds according to formula (I) or (Ia) orpreferred selections thereof, as a free base, acid, or salts thereof.Further, additionally embodiments relate to synthetic intermediates,which are useful in the synthesis of a compound of formula (I) as a freebase, acid, or salts thereof. Specific and generic examples of suchintermediates are given below. Further, such intermediates may includecompounds according to formula (I), which may be used to produce anothercompound according to formula (I).

Throughout the following description of such processes it is to beunderstood that, where appropriate, suitable protecting groups will beattached to, and subsequently removed from, the various reactants andintermediates in a manner that will be readily understood by one skilledin the art of organic synthesis. Conventional procedures for using suchprotecting groups, as well as examples of suitable protecting groups,are well known within the art. Further such procedures and groups aredescribed in the literature, such as in “Protective Groups in OrganicSynthesis”, 3rd ed., T. W. Green, P. G. M. Wuts, Wiley-Interscience, NewYork (1999).

It is also to be understood that a transformation of a group orsubstituent into another group or substituent by chemical manipulationcan be conducted on any intermediate or final product on the syntheticpath toward the final product, in which the possible type oftransformation is limited only by inherent incompatibility of otherfunctionalities carried by the molecule at that stage to the conditionsor reagents employed in the transformation. Such inherentincompatibilities, and ways to circumvent them by carrying outappropriate transformations and synthetic steps in a suitable order,will be readily understood to the one skilled in the art of organicsynthesis.

Examples of transformations are given below, and it is to be understoodthat the described transformations are not limited only to the genericgroups or substituents for which the transformations are exemplified.

References and descriptions on other suitable transformations are forexample given in “Comprehensive Organic Transformations—A Guide toFunctional Group Preparations”, 2nd ed., R. C. Larock, Wiley-VCH, NewYork (1999). References and descriptions of other suitable reactions aredescribed in textbooks of organic chemistry well known to the oneskilled in the art, such as “March's Advanced Organic Chemistry”, 5thed., M. B. Smith, J. March, John Wiley & Sons (2001) or, “OrganicSynthesis”, 2nd ed., M. B. Smith, McGraw-Hill, (2002).

In the various schemes given below, generic groups, such as R-groups,have the same representation as given above herein, if not specificallydefined.

Methods of Preparation of Final Compounds of Formula (I) by the ReactionBetween Intermediates (VI) and (VII) (Scheme 1)

Products of structure (I) maybe prepared by reacting structures of (VI)with thiols (VII) through a conjugate addition in the presence of asuitable base or acid as catalyst or in stoichiometric amounts.

Methods of Preparation of Final Compounds of Formula (I) by the ReactionBetween Intermediates (VI) and (VIII) (Scheme 2)

Products of structure (I) maybe prepared by reacting structures of (VI)with in situ generated thiols through a conjugate addition in thepresence of a suitable base or acid as catalyst or in stoichiometricamounts. The in situ generated thiols are formed by reducing thecorresponding disulfide (VIII) with an appropriate reducing agent e.g.NaBH₄, PPh₃, P(nBu)₃.

Methods of Preparation of Final Compounds of Formula (I) by the ReactionBetween Intermediates (II) and (V) (Scheme 3)

Products of structure (XII) maybe prepared by reacting structures of(VI) with amino acid thiols (IX) through a conjugate addition in thepresence of a suitable base or acid as catalyst or in stoichiometricamounts. The intermediate amino acid (X) can be alkylated or acylated onthe free nitrogen group to obtain intermediates of structure (XI). Thesecarboxylic acids can be esterified using known methods, e.g. converting(XI) to an acid chloride or using activating reagents, to give finalcompounds of structure (XII).

Methods of preparation of intermediate compounds of formula (VII) and(VIII) are described in e.g. Rayner, C. M. Contemp. Org. Synth., 1995,2, 409-440.

The synthesis of intermediates of structure (II) are described in WO2012/010555, WO 2012/011864, Org Lett. 2010 12(22), 5100-3 and JAntibiot 2002 55(7), 663-5

EXPERIMENTAL Abbreviations

-   TEA Triethyl amine-   Boc t-Butyloxycarbonyl-   eq Equivalent

COMPOUND EXAMPLES

Preparation of Intermediates

Below follows non-limiting examples on the synthesis of intermediatesuseful for the preparation of compounds of formula (I).

Preparation of Final Compounds

Below follows non-limiting examples on the synthesis of final compoundsof formula I.

General Methods

All materials were obtained from commercial sources and were usedwithout further purification unless otherwise noted. THF was distilledfrom sodium and benzophenone. NMR spectra (in CDCl₃, CD₃OD or DMSO-d6)were recorded on a Bruker DRX 400 or on a Bruker Ultrashield 400spectrometer at 400 MHz. All chemical shifts are in ppm on thedelta-scale (6) relative to TMS using the residual CHCl₃ peak in CDCl₃,or the residual CD₂HOD peak in CD₃OD, or the residual CD₃SOCD2H peak in(CD₃)₂SO as internal standard (7.26, 3.31 or 2.50 ppm respectivelyrelative to TMS) and the fine splitting of the signals as appearing inthe recordings (s: singlet, d: doublet, t: triplet, q: quartet, m:multiplet, br: broad signal). Flash chromatography was performed using60 Å 35-70 μm Davisil silica gel. TLC analyses were made on Silica Gel60 F254 (Merck) plates and visualised under a 254/365 nm UV-lamp.

Techniques for purification of intermediates and final products includefor example, straight and reversed phase chromatography on column orrotating plate, size exclusion chromatography, recrystallisation,distillation and liquid-liquid or solid-liquid extraction, which will bereadily understood by the one skilled in the art.

The terms “room temperature” and “ambient temperature” shall mean,unless otherwise specified, a temperature between 16 and 25° C. The term“reflux” shall mean, unless otherwise stated, in reference to anemployed solvent using a temperature at or slightly above the boilingpoint of the named solvent. It is understood that microwaves can be usedfor the heating of reaction mixtures.

The terms “flash chromatography” or “flash column chromatography” shallmean preparative chromatography on silica using an organic solvent, ormixtures thereof, as mobile phase.

General Procedure for the Conjugate Addition of Thiols to (Scheme 4)

0.17 mmol 1.0 eq (VI) was dissolved in 2 ml MeOH and the thiol 0.18 mmol1.1 eq (VII) was added followed by 0.017 mmol TEA 0.1 eq. The reactionmixture was stirred over night and concentrated under reduced pressure.The product (I) was purified using flash chromatography (solvent system,yield and analytical data are given for each compound).

Example 1 3β-(Butyllthio)-2aβ,3-dihydrogaliellalactone

(heptane/EtOAc 7:3)

Yield: 72%

¹H NMR (CDCl₃) δ 4.59 (m, 1H), 3.20 (m, 1H), 3.06 (m, 1H), 2.65 (s, 1H),2.61 (m, 2H), 2.23 (m, 1H), 2.12 (m, 1H), 2.08 (m, 1H), 2.00 (m, 1H),1.78 (m, 1H), 1.64 (m, 1H), 1.63 (m, 2H), 1.51 (m, 1H), 1.43 (m, 2H),1.15 (d, 3H), 0.93 (m, 3H), 0.78 (m, 1H).

HRMS: calc for C15H25O3S (M+H) 285.1524, found 285.1524

Example 2 3β-(Phenylthio)-2aβ,3-dihydrogaliellalactone

(heptane/EtOAc 7:3)

Yield: 72%

¹H NMR (CDCl₃) δ 7.45 (m, 2H), 7.34 (m, 2H), 7.25 (m, 1H), 4.50 (m, 1H),3.63 (m, 1H), 3.15 (m, 1H), 2.39 (s, 1H), 2.25 (m, 1H), 2.15 (m, 1H),2.06 (m, 1H), 2.00 (m, 1H), 1.84 (m, 1H), 1.75 (m, 1H), 1.51 (m, 1H),1.22 (d, 3H), 0.85 (m, 1H).

HRMS: calc for C17H21O3S (M+H) 305.1211, found 305.1219

Example 3 3β-(N-acetyl L-cysteine methylester)-2aβ,3-dihydrogaliellalactone

(EtOAc 100%)

Yield: 62%

¹H NMR (CDCl₃) δ 6.50 (d, 1H), 4.90 (m, 1H), 4.60 (m, 1H), 3.81 (s, 3H),3.43 (m, 1H), 3.08 (m, 2H), 3.02 (m, 1H), 2.21 (m, 1H), 2.11 (m, 1H),2.08 (s, 3H) 2.03 (m, 2H), 1.85 (m, 1H), 1.57 (m, 1H), 1.42 (m, 1H),1.13 (d, 3H), 0.74 (m, 1H).

HRMS: calc for C17H26NO6S (M+H) 372.1481, found 372.1499

Example 4 3β-(N-acetyl L-cysteine ethylester)-2aβ,3-dihydrogaliellalactone

(EtOAc 100%)

Yield: 44%

¹H NMR (CDCl₃) δ 6.59 (d, 1H), 4.86 (dd, 1H), 4.59 (t, 1H), 4.25 (m,2H), 3.41 (m, 1H), 3.08 (m, 2H), 3.00 (m, 1H), 2.20 (m, 1H), 2.10 (m,1H), 2.02 (s, 3H), 2.02 (m, 2H), 1.85 (m, 1H), 1.59 (m, 2H) 1.32 (t,3H), 1.12 (d, 3H), 0.73 (m, 1H).

HRMS: calc for C18H28NO6S (M+H) 386.1637, found 386.1623

Example 5 3β-(N-pivaloyl L-cysteine methylester)-2aβ,3-dihydrogaliellalactone

(Heptane/EtOAc 2:3)

Yield: 72%

¹H NMR (CDCl₃) δ 6.52 (d, 1H), 4.85 (m, 1H), 4.59 (m, 1H), 3.79 (s, 3H),3.47 (m, 1H), 3.06 (m, 2H), 2.99 (m, 1H), 2.47 (m, 1H), 2.19 (m, 1H),2.09 (m, 1H), 2.01 (m, 2H), 1.84 (m, 1H), 1.57 (m, 1H), 1.39 (m, 1H),1.18 (d, 3H), 1.16 (d, 3H), 1.11 (d, 3H), 0.71 (m, 1H).

HRMS: calc for C19H30NO6S (M+H) 400.1794, found 400.1780:

Example 6 3β-(N-(tert-butylcarbonate)-L-cysteine methylester)-2aβ,3-dihydrogaliellalactone

(Heptane/EtOAc 7:3)

Yield: 70%

¹H NMR (CDCl₃) δ 5.48 (d, 1H), 4.57 (m, 1H), 4.56 (d, 1H), 3.78 (s, 3H),3.37 (m, 1H), 3.05 (m, 2H), 3.01 (m, 1H), 2.20 (m, 1H), 2.09 (m, 1H),2.02 (m, 2H), 1.82 (m, 1H), 1.59 (m, 1H), 1.44 (s, 9H), 1.12 (d, 3H),0.73 (m, 1H).

HRMS: calc for C20H31NO7SNa (M+Na) 452.1719, found 452.1736

Example 7 3β-(N-acetyl L-cysteine amide)-2aβ,3-dihydrogaliellalactone

(CHCl₃/MeOH 9:1+3% acetic acid)

Yield: 65%

¹H NMR (CDCl₃) δ 7.21 (d, 1H), 4.82 (m, 1H), 4.61 (m, 1H), 3.43 (m, 1H),3.18 (m, 1H), 3.10 (m, 1H), 2.95 (d, 1H), 2.19 (m, 1H), 2.12 (m, 1H),2.01 (m, 2H), 1.88 (m, 1H), 1.64 (m, 1H), 1.38 (m, 1H), 1.11 (d, 3H),0.70 (m, 1H).

Example 8 3β-(ethyl sulphonate)-2aβ,3-dihydrogaliellalactone sodium

Purified by extraction.

Yield: quantitative

¹H NMR (CD₃OD) δ 4.52 (m, 1H), 3.40 (m, 1H), 3.15 (m, 2H), 3.03 (d, 1H),3.01 (m, 2H), 2.20 (m, 1H), 2.11 (m, 1H), 1.98 (m, 2H), 1.92 (m, 1H),1.63 (m, 1H), 1.14 (d, 3H), 0.64 (m, 1H).

Example 9 3β-(glutathione)-2aβ,3-dihydrogaliellalactone

Sephadex with MeOH/H₂O 9:1, then flashed with CHCl₃/MeOH 1:1+3% aceticacid

Yield: 62%

¹H NMR (CD₃OD+10% D₂O) δ 4.64 (m, 1H), 4.60 (m, 1H), 3.92 (s, 2H), 3.83(t, 1H), 3.42 (m, 1H), 3.15 (m, 1H), 2.98 (m, 1H), 2.87 (m, 1H), 2.55(m, 2H), 2.19 (m, 1H), 2.15 (m, 1H), 2.11 (m, 1H), 1.99 (m, 2H), 1.92(m, 1H), 1.65 (m, 1H), 1.27 (m, 1H), 1.22 (d, 3H), 0.62 (m, 1H).

Example 10 3β-(N-acetyl L-cysteine i-propylester)-2aβ,3-dihydrogaliellalactone

(EtOAc 100%)

Yield: 11%

¹H NMR (CDCl₃) δ 6.52 (d, 1H), 5.09 (m 1H), 4.81 (m, 1H), 4.59 (m 1H),3.45 (m, 1H), 3.07 (m, 2H), 3.04 (m, 1H), 2.21 (m, 1H), 2.08 (s, 3H),2.05 (m, 1H), 2.02 (m, 2H), 1.85 (m, 1H), 1.59 (m, 1H), 1.42 (m, 1H),1.31 (d, 3H), 1.30 (d, 3H), 1.13 (d, 3H), 0.74 (m, 1H).

Example 11 3β-(N-acetyl L-cysteine methylester)-2aβ,3-dihydro-7-phenyl-galiellalactone

¹H NMR (CDCl₃) δ 7.33 (m, 2H), 7.31 (m, 2H), 7.25 (m, 1H), 6.62 (d, 1H),4.88 (m, 1H), 4.64 (d, 1H), 3.79 (s, 3H), 3.53 (m, 1H), 3.53 (m, 1H),3.12 (m, 1H), 3.07 (m, 1H), 3.01 (m, 1H), 2.54 (m, 1H), 2.26 (m, 1H),2.09 (s, 3H), 1.99 (m, 1H), 1.69 (m, 1H), 1.61 (1H, m), 1.17 (d, 3H),0.82 (m, 1H).

Example 12 3β-(N-acetyl-L-homocysteine methylester)-2aβ,3-dihydrogaliellalactone

30 mg galiellalactone (0.154 mmol) was dissolved in 3 ml MeOH. 25 mghomo-cysteine (0.17 mmol) was added followed by 2 □l TEA (0.015 mmol).The reaction mixture was stirred over night at room temperature. Thevolatiles were removed under reduced pressure. The crude product wasdissolved in 5 ml CH₂C12 and 27 □l TEA (0.289 mmol) was added. Thesolution was stirred for 15 min and then cooled to 0° C. 17 □l acetylchloride (0.238 mmol) was added and the reaction mixture was stirred at0° C. for 2.5 h. The volatiles were removed under reduced pressure andthe crude was dissolved in 2 ml MeOH. The solution was cooled to 0° C.and then 30 □l thionyl chloride was added. The reaction mixture wasstirred at room temperature over night. The volatiles were removed underreduced pressure and flash chromatography (100% EtOAc) afforded 24 mg(40%) of the title compound.

¹H NMR (CD₂Cl₂) 6 6.47 (d, 1H), 4.68 (m, 1H), 4.55 (m, 1H), 3.74 (s,3H), 3.41 (m, 1H), 2.96 (m, 1H), 2.71 (m, 2H), 2.18 (m, 1H), 2.17 (m,2H), 2.10 (m, 2H), 2.07 (m, 2H), 2.00 (s, 3H), 1.98 (m, 2H), 1.87 (m,1H), 1.67 (m, 1H), 1.36 (m, 1H), 1.13 (d, 3H), 0.69 (m, 1H).

HRMS: calc for C18H27NO6SNa (M+Na) 408.1457, found 408.1454.

N-(2-fluorobenzoyl)-L-cysteine methyl ester

300 mg L-cysteine methyl ester hydrochloride (1.74 mmol) is dissolved in20 ml CH2Cl2. 0.25 ml TEA (2.61 mmol) is added under N2 and then thesolution is cooled to 0° C. followed by addition of 0.23 ml2-fluorobenzoyl chloride (1.92 mmol). The reaction mixture is stirredover night and then NaHCO₃ (sat.) is added and the resulting mixture isextracted three times with EtOAc. The combined organic phases are fried(Na2SO4) and the volatiles are removed under reduced pressure. The crudeproduct is used directly in the next step.

Example 13 3β-(N-(2-fluorobenzoyl)-L-cysteine methylester)-2aβ,3-dihydrogaliellalactone

20 mg galiellalactone (0.103 mmol) was dissolved in 2 ml MeOH. 60 mgN-(2-fluorobenzoyl)-L-cysteine methyl ester (0.257 mmol) was addedfollowed by 2 □l TEA (0.015 mmol). The reaction mixture was stirred overnight at room temperature. The volatiles were removed under reducedpressure and flash chromatography (heptane/EtOAc 7:3) afforded 31 mg(67%) of the title compound.

¹H NMR (CDCl₃) δ 8.04 (m, 1H), 7.64 (d, 1H), 7.51 (m, 1H), 7.27 (m, 1H),7.15 (m, 1H), 5.09 (m, 1H), 4.57 (m, 1H), 3.84 (s, 3H), 3.45 (m, 1H),3.21 (m, 2H), 3.03 (m, 1H), 2.19 (m, 1H), 2.09 (m, 1H), 2.02 (m, 2H),1.81 (m, 1H), 1.58 (m, 1H), 1.41 (m, 1H), 1.11 (d, 3H), 0.72 (m, 1H).

HRMS: calc for C22H27FNO6S (M+H) 452.1543, found 452.1520

3β-(N—(N-Boc-L-valine)-L-cysteine methylester)-2aβ,3-dihydrogaliellalactone

A solution of 138 mg N-Boc-valine-cysteine (0.411 mmol) in 1.5 ml MeOHis added to a solution of 20 mg galiellalactone (0.103 mmol) in 1.5 mlMeOH followed by 4 □l TEA (0.03 mmol). The reaction mixture is stirredover night and then the volatiles are removed under reduced pressure.The crude is purified by flash chromatography (heptane/EtOAc 7:3) togive 32 mg of the Boc-protected title compound.

Example 14 3β-(N-(L-valine)-L-cysteine methylester)-2aβ,3-dihydrogaliellalactone

56 mg 3β-(N—(N-Boc-L-valine)-L-cysteine methylester)-2aβ,3-dihydrogaliellalactone (0.182 mmol) is dissolved in 3 mldiethyl ether. 4 ml 1M HCl in diethyl ether is slowly added. After 24 hthe volatiles are removed and the remains are dissolved in CH₂C12/Et2O1:1. The solution is cooled with an ice bath and the formed precipitateis collected by filtration. The filtrate is purified by flashchromatography (CH2Cl2 10% MeOH) to yield 30 mg (74%) of the titleproduct.

HRMS: calc for C20H33N2OS (M+H) 429.2059, found 429.2067

Example 15 4 □-fluoro-galiellalactone

Iso-galiellalactone

1.6 g (10.30 mmol) 1,8-Diazabicyclo[5.4.0]undec-7-ene (DBU) was added toa solution of 500 mg (2.57 mmol) galiellalactone in CH₂Cl₂ and stirredovernight at room temperature. Purification with flash chromatography(heptane/EtOAc 7:3), afforded 450 mg of iso-galiellalactone. (90%)

¹H NMR (CDCl₃) δ 5.05 (m, 1H), 4.78 (m, 1H), 3.19 (s, 1H), 2.85 (m, 1H),2.37 (m, 1H), 2.21 (m, 1H), 1.95 (m, 1H), 1.90 (m, 1H), 1.90 (m, 1H),1.76 (s, 1H), 1.65 (m, 1H), 1.42 (m, 1H)

4□-fluoro-galiellalactone

Iso-galiellalactone was dissolved in CH₂Cl₂ and 1.5 mmol (1.5 eq)N-phenyl selenyl phthalimide was added followed by 6 mmol (6 eq)TEA-3HF. The reaction mixture was stirred at room temperature overnightdiluted with diethyl ether and washed with NaHCO₃ (aq). The organicphase was dried and concentrated under reduced pressure.

To a solution of resulting crude selenylated product (38 mg, 0.1 mmol)in 2 ml of CH₂Cl₂ was added H₂O₂ (12 uL) at 0° C. under N₂, and stirredfor 3 h. The reaction was quenched by 2 ml NaHCO₃ sat at 0° C. andextracted with CH₂C12 (5 ml×3), dried with MgSO₄ and concentrated underreduced pressure. Purification with flash chromatography (heptane/EtOAc7:3), afforded 16 mg of the 4□-fluoro-galiellalactone. (65%)

¹H NMR (CDCl₃) δ 6.91 (d, 1H), 4.86 (d, 1H), 2.42 (m, 1H), 2.29 (m, 1H),2.19 (m, 1H), 2.14 (m, 1H), 1.80 (m, 1H), 1.75 (m, 1H), 1.61 (d, 3H),1.60 (m, 1H)

Example 16 4□-fluoro-3β-(N-acetyl L-cysteine methylester)-2aβ,3-dihydro-galiellalactone

15 mg 4 □□fluoro-galiellalactone (0.071 mmol) was dissolved in 2 mlMeOH. 14 mg N-acetyl-L-cysteine methyl ester (0.078 mmol) was addedfollowed by 2 □l TEA (0.015 mmol). The reaction mixture was stirred overnight at room temperature. The volatiles were removed under reducedpressure and flash chromatography (heptane/EtOAc 7:3) afforded 12 mg(43%) of the title compound.

¹H NMR (CDCl₃) δ 6.64, (d, 1H), 4.90 (m, 1H), 4.65 (m, 1H), 3.47 (m,1H), 3.43 (m, 1H), 3.21 (m, 1H), 3.12 (m, 1H), 2.24 (m, 1H), 2.07 (s,3H), 2.05 (m, 1H), 1.96 (m, 1H), 1.90 (m, 1H) 1.83 (m, 1H), 1.81 (m,1H), 1.80 (m, 1H), 1.57 (s, 3H)

BIOLOGICAL EXAMPLES Biological Example

The usefulness of the compounds, as defined in the embodiments herein,as prodrugs to enhance the plasma exposure of tricyclic compounds thatmay be used treating, revoking, mitigating, alleviating and/orpreventing different forms of cancer, were evaluated in an in vivopharmacokinetic (PK) study in mice.

Example 17 Pharmacokinetic (PK) Study

Doses of the test items were prepared at a drug concentration of 0.5mg/mL in 5% DMSO in 50 mM citrate buffer (citric acid/sodium citrate),pH 4.0.

Oral doses were administered in a volume of 20 mL/kg (10 mg/kg) togroups of 24 mice and blood samples taken, under terminal barbiturateanaesthesia, at eight time-points out to 8 hours post-dose (n=3 mice pertime-point).

Blood samples were transferred to tubes containing EDTA as anticoagulantand, as soon as practicable after collection, samples were centrifugedto yield plasma which was immediately frozen awaiting analysis.Following blood collection, brains were removed from all animals forpossible future analysis and immediately frozen by immersion in liquidnitrogen. All samples were analyzed using LC-MS/MS.

Plasma Sample Analysis

Plasma proteins were precipitated and compounds extracted by theaddition of three volumes of acetonitrile containing analytical internalstandard (reserpine). Samples were centrifuged for 30 minutes at 3452 gin a Sorvall bench centrifuge and the supernatant fractions removed forMS analysis.

Quantification of the active compound e.g. galiellalactone, was byextrapolation from calibration lines prepared in control mouse plasmaand analyzed concurrently with experimental samples and Quality Control(QC) samples prepared in control mouse plasma. If the compounds wereinstable in mouse plasma, calibration lines were constructed in waterfor qualitative MS comparison with any signal seen in plasma samples.

Pharmacokinetic Analysis

Pharmacokinetic parameters of the test items were determined using themean data from the n=3 mice at each time-point. Non-compartmentalanalysis was performed using the software package PK Solutions 2.0 fromSummit Research Services. AUC values were calculated by the trapezoidalmethod.

Definition of Terms

AUC 0-t: Area under the plasma drug concentration/time curve from 0minutes to last quantifiable data point

AUC 0-∞: Area under the curve from 0 minutes extrapolated to infinity

GL: Galiellalactone

TABLE 1 Pharmacokinetic parameters of examples AUC 0-t (μg AUC 0-∞ (μgCompound GL/mL · min) GL/mL · min) Galiellalactone 5 6 (control) Example1 85 102 Example 2 36 41 Example 4 20 22 Example 5 15 21 Example 13 7.811 Example 6 11 17 Example 12 150 155 Example 14 97 101 Example 3 117120

2.2 2.5

As can be seen from table 1, oral administration of prodrug compoundsdefined by the claims increases the plasma exposure over time (AUC) ofgaliellalactone compared to oral administration of galiellalactoneitself. Noteworthy is that amine adducts, as exemplified by3β-(N-pyrrolidine)-2aβ,3-dihydrogaliellalactone, do not increase theAUC.

Example 18 Chemical Stability in Phosphate Buffered Saline

The chemical stability of test compounds was determined in 96-well plateformat. Compounds in DMSO stock solutions were diluted (n=2) in therequired matrix (0.1 M phosphate buffered saline) to a concentration of10 μM (2% DMSO final) and mixed at room temperature on an orbitalshaker, with aliquots removed at 2 and 4 hours for testing. DMSO,containing an analytical internal standard, was added to the aliquots,vortex-mixed and analysed immediately by LC-MS/MS. Equivalent T=0samples were also included, with sample preparation staggered to allowsequential injections of timed aliquots and the T=0 samples.

The amount of compound remaining (expressed as %) was determined fromthe MS response in each sample relative to that in the T=0 samples(normalized for internal standard).

Ln plots of the % remaining were used to determine the half-life ofcompound disappearance from the relationship:

t_(1/2) (min)=−0.693/λ, where λ is the slope of the Ln concentration vstime curve.

TABLE 2 half-life of compound for selected compounds in PBS Half-life(min) 0.1 M Compound PBS pH 7.4

22

14

18 Example 3 >150 Example 5 >138 Example 6 >150 Example 14 66 Example7 >150 Example 8 >150 Example 9 >150

As can be seen in table 2 the adducts of cysteine and galiellalactoneand cysteine Me-ester and galiellalactone had low stability in PBSbuffer (t½<30 min). This is comparable to the low stability of thepyrrolidine adduct 3β-(N-pyrrolidine)-2aβ,3-dihydrogaliellalactone whichdid not provide any improved in vivo plasma exposure of galiellalactonefollowing oral administration (cf. Table 1). It is thus concluded thatthese adducts, which have low chemical stability, will not function aseffective prodrugs. On the contrary, compounds defined by the claimshave significantly increased chemical stability, which correlates wellwith their improved in vivo plasma exposure (cf. Table 1). Thus they areeffective as prodrugs.

Example 19 Anti-Proliferative Activity of Example 15(4□-fluoro-galiellalactone)

WST-1 Cell Proliferation Assay

The functional activity of example 15 in comparison to galiellalactonewas evaluated using WST-1 proliferation assay (J. Biol. Chem. 2014,289:15969-15978) on DU145, PC-3, LNCaP or IL-6 stimulated LNCaP. Thecells were cultured in 96-well plates (2000 cells/well in 200 μl ofmedium) and allowed to set for 24 h. The cells were treated with 10 μMof 4α-fluoro-galiellalactone or galiellalactone for 72 h. Samples weremade in triplicate. 20 μl WST-1 solution (Roche Applied Science) wasadded per well and incubated at 37° C. for 4 h. The absorbance of eachwell was measured using a scanning multi-well spectrophotometer, ELISAreader at a wavelength of 450 nm and reference wavelength of 690 nm. Theresults presented in Table 3 below are presented as percent of untreatedcontrol cells.

Western Blot Analysis of pSTAT3 in Prostate Cancer Cells

Samples were separated on 7.5% precast gel (Mini-PROTEAN TGX; Bio-Rad)or 8% Tris Bis self cast gels. The gels were blotted onto PVDF membranesand blocked with 5% milk or 5% BSA. Membranes were incubated withprimary antibody diluted in 5% milk or 5% BSA for 1 h at roomtemperature or over night at 4° C. with antibodies raised against STAT3,pSTAT3 tyr-705 or pSTAT3 ser-727 (Cell Signaling Technology).

After incubation with secondary anti-mouse or anti-rabbit antibodyconjugated with horseradish peroxidase (GE Healthcare Life Sciences) themembrane was treated with enhanced chemiluminescent reagent (Santa CruzBiotechnology or Millipore) followed by exposure to X-Ray film orvisualized using a Chemidoc XRS system (Bio-Rad).

TABLE 3 Proliferation of pSTAT3 cell lines in the presence ofgaliellalactone and 4□-fluoro-galiellalactone % Remaining Proliferation4α- Time/ Cell pSTAT3 fluoro- dose type expression Galiellalactonegaliellalactone 72 DU145 + 18 16 hours/ PC3 − 31 68 10 μM LNCaP − 77 105LNCaP- + 17 20 IL6

Table 3 shows that proliferation of the pSTAT3 negative cell lines PC3and LNCaP are less affected by 4α-fluoro-galiellalactone thangaliellalactone (both at 10 μM). On the other hand, the pSTAT3 positivecells are equally sensitive to 4α-fluoro-galiellalactone andgaliellalactone. This shows that 4α-fluoro-galiellalactone issignificantly more selective for STAT3 than is galiellalactone.

1-17. (canceled)
 18. A compound according to formula (Ia),

wherein R₁ is halo; R₁′ is selected from the group consisting of H, C1-5alkyl, C1-5 fluoroalkyl, halo, C3-8 non-aromatic carbocycle, C0-5alkyleneOC0-5 alkyl, C0-3 alkyleneOC1-5 fluoroalkyl, C0-3alkyleneOC(O)C1-5 alkyl, OC2-3 alkyleneN(C0-5 alkyl)₂ in which the C0-5alkyl may be the same or different, C0-3 alkyleneNHC0-5 alkyl, C0-3alkyleneN(C1-5 alkyl)₂ in which the C1-5 alkyl may be the same ordifferent, C0-3 alkyleneN(C0-5 alkyl)C(O)C1-5 alkyl, C0-3alkyleneNHaryl, wherein the aryl is unsubstituted or substituted with aone or several substituents independently selected from the groupconsisting of C1-5 alkyl, C1-5 fluoroalkyl, halo, C0-5 alkyleneOC0-5alkyl, nitro, cyano and N(C0-5 alkyl)₂ in which the C0-5 alkyl may bethe same or different, C0-3 alkyleneNHheteroaryl, wherein saidheteroaryl is a 5- or 6-membered heteroaryl, said heteroaryl beingunsubstituted or substituted with a one or several independentlyselected C1-5 alkyl groups, C0-3 alkyleneC(O)NHC0-5 alkyl, C0-3alkyleneC(O)N(C1-5 alkyl)₂ in which the C1-5 alkyl may be the same ordifferent, C0-3 alkyleneC(O)N(C4-5 alkylene), C0-3 alkyleneC(O)OC0-5alkyl, a 3- to 8-membered non-aromatic heterocycle, C0-3 alkylene aryl,wherein the aryl is unsubstituted or substituted with a one or severalsubstituents independently selected from the group consisting of C1-5alkyl, C1-5 fluoroalkyl, halo, C0-5 alkyleneOC0-5 alkyl, nitro, cyanoand N(C0-5 alkyl)₂ in which the C0-5 alkyl may be the same or different,C0-3 alkylene heteroaryl, wherein said heteroaryl is a 5- or 6-memberedheteroaryl, said heteroaryl being unsubstituted or substituted with aone or several independently selected C1-5 alkyl groups, halo, C0-1alkylene cyano, SC0-5 alkyl, C0-3 alkyleneSO₂C0-5 alkyl, nitro,C(O)C0-C5 alkyl, C(O)C1-C5 fluoroalkyl, N(C0-C3 alkyl)SO₂C1-C5 alkyl,and N(C0-C5 alkyl)SO₂C1-5 fluoroalkyl; R₂ and R₂′ are independentlyselected from the group consisting of H, C1-5 alkyl, C1-5 fluoroalkyl,halo, C3-8 non-aromatic carbocycle, C0-5 alkyleneOC0-5 alkyl, C0-3alkyleneOC1-5 fluoroalkyl, C0-3 alkyleneOC(O)C1-5 alkyl, OC2-3alkyleneN(C0-5 alkyl)₂ in which the C0-5 alkyl may be the same ordifferent, C0-3 alkyleneNHC0-5 alkyl, C0-3 alkyleneN(C1-5 alkyl)₂ inwhich the C1-5 alkyl may be the same or different, C0-3 alkyleneN(C0-5alkyl)C(O)C1-5 alkyl, C0-3 alkyleneNHaryl, wherein the aryl isunsubstituted or substituted with a one or several substituentsindependently selected from the group consisting of C1-5 alkyl, C1-5fluoroalkyl, halo, C0-5 alkyleneOC0-5 alkyl, nitro, cyano and N(C0-5alkyl)₂ in which the C0-5 alkyl may be the same or different, C0-3alkyleneNHheteroaryl, wherein said heteroaryl is a 5- or 6-memberedheteroaryl, said heteroaryl being unsubstituted or substituted with aone or several independently selected C1-5 alkyl groups, C0-3alkyleneC(O)NHC0-5 alkyl, C0-3 alkyleneC(O)N(C1-5 alkyl)₂ in which theC1-5 alkyl may be the same or different, C0-3 alkyleneC(O)N(C4-5alkylene), C0-3 alkyleneC(O)OC0-5 alkyl, a 3- to 8-membered non-aromaticheterocycle, C0-3 alkylene aryl, wherein the aryl is unsubstituted orsubstituted with a one or several substituents independently selectedfrom the group consisting of C1-5 alkyl, C1-5 fluoroalkyl, halo, C0-5alkyleneOC0-5 alkyl, nitro, cyano and N(C0-5 alkyl)₂ in which the C0-5alkyl may be the same or different, C0-3 alkylene heteroaryl, whereinsaid heteroaryl is a 5- or 6-membered heteroaryl, said heteroaryl beingunsubstituted or substituted with a one or several independentlyselected C1-5 alkyl groups, halo, C0-1 alkylene cyano, SC0-5 alkyl, C0-3alkyleneSO₂C0-5 alkyl, nitro, C(O)C0-C5 alkyl, C(O)C1-C5 fluoroalkyl,N(C0-C3 alkyl)SO₂C1-C5 alkyl, and N(C0-C5 alkyl)SO₂C1-5 fluoroalkyl; R₃and R₃′ are independently selected from the group consisting of H, C1-5alkyl, C1-5 fluoroalkyl, halo, C3-8 non-aromatic carbocycle, C0-5alkyleneOC0-5 alkyl, C0-3 alkyleneOC1-5 fluoroalkyl, C0-3alkyleneOC(O)C1-5 alkyl, OC2-3 alkyleneN(C0-5 alkyl)₂ in which the C0-5alkyl may be the same or different, C0-3 alkyleneNHC0-5 alkyl, C0-3alkyleneN(C1-5 alkyl)₂ in which the C1-5 alkyl may be the same ordifferent, C0-3 alkyleneN(C0-5 alkyl)C(O)C1-5 alkyl, C0-3alkyleneNHaryl, wherein the aryl is unsubstituted or substituted with aone or several substituents independently selected from the groupconsisting of C1-5 alkyl, C1-5 fluoroalkyl, halo, C0-5 alkyleneOC0-5alkyl, nitro, cyano and N(C0-5 alkyl)₂ in which the C0-5 alkyl may bethe same or different, C0-3 alkyleneNHheteroaryl, wherein saidheteroaryl is a 5- or 6-membered heteroaryl, said heteroaryl beingunsubstituted or substituted with a one or several independentlyselected C1-5 alkyl groups, C0-3 alkyleneC(O)NHC0-5 alkyl, C0-3alkyleneC(O)N(C1-5 alkyl)₂ in which the C1-5 alkyl may be the same ordifferent, C0-3 alkyleneC(O)N(C4-5 alkylene), C0-3 alkyleneC(O)OC0-5alkyl, a 3- to 8-membered non-aromatic heterocycle, C0-3 alkylene aryl,wherein the aryl is unsubstituted or substituted with a one or severalsubstituents independently selected from the group consisting of C1-5alkyl, C1-5 fluoroalkyl, halo, C0-5 alkyleneOC0-5 alkyl, nitro, cyanoand N(C0-5 alkyl)₂ in which the C0-5 alkyl may be the same or different,C0-3 alkylene heteroaryl, wherein said heteroaryl is a 5- or 6-memberedheteroaryl, said heteroaryl being unsubstituted or substituted with aone or several independently selected C1-5 alkyl groups, halo, C0-1alkylene cyano, SC0-5 alkyl, C0-3 alkyleneSO₂C0-5 alkyl, nitro,C(O)C0-C5 alkyl, C(O)C1-C5 fluoroalkyl, N(C0-C3 alkyl)SO₂C1-C5 alkyl,and N(C0-C5 alkyl)SO₂C1-5 fluoroalkyl; and R₄ and R₄′ are independentlyselected from the group consisting of H, C1-5 alkyl, C1-5 fluoroalkyl,halo, C3-8 non-aromatic carbocycle, C0-5 alkyleneOC0-5 alkyl, C0-3alkyleneOC1-5 fluoroalkyl, C0-3 alkyleneOC(O)C1-5 alkyl, OC2-3alkyleneN(C0-5 alkyl)₂ in which the C0-5 alkyl may be the same ordifferent, C0-3 alkyleneNHC0-5 alkyl, C0-3 alkyleneN(C1-5 alkyl)₂ inwhich the C1-5 alkyl may be the same or different, C0-3 alkyleneN(C0-5alkyl)C(O)C1-5 alkyl, C0-3 alkyleneNHaryl, wherein the aryl isunsubstituted or substituted with a one or several substituentsindependently selected from the group consisting of C1-5 alkyl, C1-5fluoroalkyl, halo, C0-5 alkyleneOC0-5 alkyl, nitro, cyano and N(C0-5alkyl)₂ in which the C0-5 alkyl may be the same or different, C0-3alkyleneNHheteroaryl, wherein said heteroaryl is a 5- or 6-memberedheteroaryl, said heteroaryl being unsubstituted or substituted with aone or several independently selected C1-5 alkyl groups, C0-3alkyleneC(O)NHC0-5 alkyl, C0-3 alkyleneC(O)N(C1-5 alkyl)₂ in which theC1-5 alkyl may be the same or different, C0-3 alkyleneC(O)N(C4-5alkylene), C0-3 alkyleneC(O)OC0-5 alkyl, a 3- to 8-membered non-aromaticheterocycle, C0-3 alkylene aryl, wherein the aryl is unsubstituted orsubstituted with a one or several substituents independently selectedfrom the group consisting of C1-5 alkyl, C1-5 fluoroalkyl, halo, C0-5alkyleneOC0-5 alkyl, nitro, cyano and N(C0-5 alkyl)₂ in which the C0-5alkyl may be the same or different, C0-3 alkylene heteroaryl, whereinsaid heteroaryl is a 5- or 6-membered heteroaryl, said heteroaryl beingunsubstituted or substituted with a one or several independentlyselected C1-5 alkyl groups, halo, C0-1 alkylene cyano, SC0-5 alkyl, C0-3alkyleneSO₂C0-5 alkyl, nitro, C(O)C0-C5 alkyl, C(O)C1-C5 fluoroalkyl,N(C0-C3 alkyl)SO₂C1-C5 alkyl, and N(C0-C5 alkyl)SO₂C1-5 fluoroalkyl; asa free base, an acid in its non-charged protonated form, apharmaceutically acceptable addition salt, solvate, solvate of a saltthereof, a pure diastereomer, a pure enantiomer, a diastereomericmixture, a racemic mixture, a scalemic mixture, a correspondingtautomeric form resulting from a hydrogen shift between two hetero-atomsand/or the corresponding tautomeric form resulting from a keto-enoltautomerization.
 19. The compound according to claim 18, wherein thecompound has the relative or absolute stereochemistry according toformula (Ma),


20. The compound according to claim 18, wherein R₁′, R₂, R₂′, R₃, R₃′,R₄ and R₄′ are independently selected from the group consisting of H,C1-5 alkyl, halo, aryl, wherein the aryl is unsubstituted or substitutedwith a one or several substituents independently selected from the groupconsisting of C1-5 alkyl, C1-5 fluoroalkyl, halo, C0-5 alkyleneOC0-5alkyl, nitro, cyano and N(C0-5 alkyl)₂ in which the C0-5 alkyl may bethe same or different, CH₂aryl, wherein the aryl is unsubstituted orsubstituted with a one or several substituents independently selectedfrom the group consisting of C1-5 alkyl, C1-5 fluoroalkyl, halo, C0-5alkyleneOC0-5 alkyl, nitro, cyano and N(C0-5 alkyl)₂ in which the C0-5alkyl may be the same or different, heteroaryl, wherein said heteroarylis a 5- or 6-membered heteroaryl, said heteroaryl being unsubstituted orsubstituted with a one or several independently selected C1-5 alkylgroups, and CH₂heteroaryl, wherein said heteroaryl is a 5- or 6-memberedheteroaryl, said heteroaryl being unsubstituted or substituted with aone or several independently selected C1-5 alkyl groups.
 21. Thecompound according to claim 18, wherein R₁ is fluorine.
 22. The compoundaccording to claim 18, wherein R₁′ is selected from the group consistingof H, C1-5 alkyl, C1-5 fluoroalkyl, halo, aryl, CH₂aryl, heteroaryl andCH₂heteroaryl.
 23. The compound according to claim 18, wherein R₁′ isC1-5 alkyl, preferably methyl.
 24. The compound according to claim 18,wherein R₂, R₂′, R₃, R₃′, R₄ and R₄′ are independently selected from thegroup consisting of H, C1-5 alkyl, aryl, CH₂aryl, heteroaryl andCH₂heteroaryl.
 25. The compound according to claim 18, wherein R₂, R₂′,R₃, R₃′, R₄ and R₄′ are H.
 26. The compound according to claim 18,wherein R₁ is fluorine; is methyl; and R₂, R₂′, R₃, R₃′, R₄, and R₄′ areH.
 27. The compound according to claim 18, wherein said compound is


28. A pharmaceutical composition comprising a compound according toclaim 18 and at least one pharmaceutically acceptable carrier orexcipient.
 29. The pharmaceutical composition according to claim 28,wherein said composition further comprises at least one additionaltherapeutic agent.
 30. (canceled)
 31. A method of treating a STAT3signaling related disorder, wherein said method comprises administeringto a subject in need thereof a compound according to claim
 18. 32. Amethod of treating a disease or disorder in a subject in need thereof,wherein the method comprises administering to the subject a compoundaccording to claim 18, said disease or disorder being selected from thegroup consisting of: solid cancers, hematological cancers, benigntumors, hyperproliferative diseases, inflammations, autoimmune diseases,graft or transplant rejections, delayed physiological function of graftsor transplants, neurodegenerative diseases and viral infections, such asfrom solid cancers and hematological cancers.
 33. The method accordingto claim 32, wherein said disease or disorder is cancer selected fromthe group consisting of: leukemia, lymphomas, multiple myeloma, breastcancer, prostate carcinoma, lung cancer (non-small-cell), renal cellcarcinoma lung cancer, hepatocellular carcinoma, cholangiocarcinoma,ovarian carcinoma, pancreatic adenocarcinoma, melanoma, and head andneck squamous cell carcinoma.
 34. The compound according to claim 23,wherein R₁′ is methyl.